Compounds and methods

ABSTRACT

Disclosed is a compound of having the formula:  
                 
pharmaceutically acceptable salts or solvates thereof and pharmaceutical compositions containing the same, wherein the structural variables are as defined herein. The compounds, salts and solvates of this invention are useful as LXR agonists.

FIELD OF THE INVENTION

The present invention relates to compounds useful as modulating agentsfor liver X receptors (LXR). Additionally, the present invention relatesto pharmaceutical formulations comprising such compounds, and thetherapeutic use of the same.

BACKGROUND OF THE INVENTION

LXR is a transcription factor. The orphan nuclear receptors, LXRα andLXRβ (collectively LXR) play a role in the maintenance of cholesterolbalance. Peet et al., Curr. Opin. Genet. Dev. 8:571-575 (1998). Inaddition, LXR binds to the ATP Binding Cassette Transporter-1 (ABCA1)gene and increases expression of the gene to result in increased ABCA1protein. ABCA1 is a membrane bound transport protein that is involved inthe regulation of cholesterol efflux from extrahepatic cells ontonascent HDL particles. Mutations in the ABCA1 gene are responsible forgenetic diseases that result in the complete absence or low levels ofHDL cholesterol and a concomitant highly increased risk ofcardiovascular disease. See Brooks-Wilson et al., Nat. Genet. 22:336-345(1999); Bodzioch et al., Nat. Genet. 22: 347-351 (1999); and Rust etal., Nat. Genet. 22:352-355 (1999). ABCA1 knockout mice homozygous forthe mutation in the ABCA1 gene have virtually no plasma HDL, whereas theheterozygotes produce 50% of the HDL of wild type animals. See, Orso etal., Nat. Genet. 24:192-196 (2000) and McNeish et al., Proc. Natl. Acad.Sci. USA 97:4245-4250 (2000). ABCA1 knockout mice also show increasedcholesterol absorption. See, McNeish et al., Proc. Natl. Acad. Sci. USA97:4245-4250 (2000). Increased expression of ABCA1 results in increasedHDL cholesterol, decreased absorption of cholesterol, and increasedremoval of excess cholesterol from extrahepatic tissues, includingmacrophages. LXR agonists also upregulate macrophage expression ofapolipoprotein E and ABCG1, both of which contribute to the efflux ofcellular cholesterol. By stimulating macrophage cholesterol effluxthrough upregulation of ABCA1, ABCG1, and apoE expression, as well asincreasing the expression of other target genes including cholesterylester transfer protein and lipoprotein lipase, LXR agonists influenceplasma lipoproteins.

Accordingly, compounds which function as LXR modulating agents, andparticularly as LXR agonists, would be useful in methods of increasingABCA1, ABCG1, and apolipoprotein E expression, increasing cholesterolefflux from peripheral cells, and treating LXR mediated diseases andconditions such as cardiovascular disease and inflammation.

SUMMARY OF THE INVENTION

This invention is directed to a compound of Formula I:

wherein:

-   -   X is CH or N;    -   Y is N(R¹⁰), O, or S, wherein t is 0 or 1 when Y is N(R¹⁰) or O,        and t is 0 when Y is S;    -   U is selected from halo, —OR¹⁰, —NR¹⁴R¹⁵, nitro, cyano, —COOR¹⁰,        —COR¹³, —OCOR¹³, —CONR¹⁴R¹⁵, —N(R¹⁴)COR¹³, —SO₃H, —SO₂NR¹⁴R¹⁵,        —C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁴)SO₂R¹⁶, and a 5 or 6-membered        heterocyclic group;    -   A is a phenyl fused ring moiety or a pyridyl fused ring moiety,        wherein when A is a phenyl ring moiety, k is 0-3 and t is 0 or 1        and when A is a pyridyl ring moiety, k is 0-2 and t is 0;    -   W¹ is selected from C₃-C₈ cycloalkyl, aryl and Het, wherein said        C₃-C₈ cycloalkyl, Ar and Het are optionally unsubstituted or        substituted with one or more groups independently selected from        halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,        —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆        alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³,        —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆        alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR¹³, where said        C₁-C₆ alkyl, is optionally unsubstituted or substituted by one        or more halo substituents;    -   W² is selected from H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆        alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆        alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆        alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆        alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents,        and wherein the C₃-C₇ cycloalkyl, Ar and Het moieties of said        —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl are optionally unsubstituted or substituted with one        or more groups independently selected from halo, cyano, nitro,        C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰,        —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆        alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆        alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆        alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆        alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆        alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally        unsubstituted or substituted by one or more halo substituents;    -   W³ is selected from the group consisting of: H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆        alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆        alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹ CONR¹¹R¹², —C₀-C₆        alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar and —C₁-C₆        alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents;    -   Q is selected from C₃-C₈ cycloalkyl, Ar and Het; wherein said        C₃-C₈ cycloalkyl, Ar and Het are optionally unsubstituted or        substituted with one or more groups independently selected from        halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,        —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀C₆        alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³,        —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆        alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR¹³, where said        C₁-C₆ alkyl is optionally unsubstituted or substituted by one or        more halo substituents;    -   p is 0-8;    -   n is 2-8;    -   m is 0 or 1;    -   q is 0 or 1;    -   t is 0 or 1;    -   each R¹ and R² are independently selected from H, halo, C₁-C₆        alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-Het, —C₁-C₆        alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹ and R²        together with the carbon to which they are attached form a 3-5        membered carbocyclic or heterocyclic ring, wherein said        heterocyclic ring contains one, or more heteroatoms selected        from N, O, and S, where said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents;    -   each R³ is the same or different and is independently selected        from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆        alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇        cycloalkyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆        alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R^(10 l , —C) ₀-C₆        alkyl-SOR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹²,        —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR¹³, wherein said        C₁-C₆ alkyl is optionally unsubstituted or substituted by one or        more halo substituents;    -   each R⁴ and R⁵ is independently selected from H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R⁶ and R⁷ are each independently selected from H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R⁸ and R⁹ are each independently selected from H. halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R¹⁰ is selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆        alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆        alkyl-C₃-C₇ cycloalkyl;    -   each R¹¹ and each R¹² are independently selected from H, C₁-C₆        alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆        alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹¹ and R¹²        together with the nitrogen to which they are attached form a 4-7        membered heterocyclic ring which optionally contains one or more        additional heteroatoms selected from N, O, and S;    -   R¹³ is selected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,        —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆ alkyl,        C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het,        —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-O—Ar, —C₀-C₆        alkyl-O-Het, —C₀-C₆ alkyl-O—C₃-C₇ cycloalkyl, —C₀-C₆        alkyl-S(O)_(x)-C₁-C₆ alkyl, —C₀-C₆ alkyl-S(O)_(x)—Ar, —C₀-C₆        alkyl-S(O)_(x)-Het, —C₀-C₆ alkyl-S(O)_(x)-C₃-C₇ cycloalkyl,        —C₀-C₆ alkyl-NH—Ar, —C₀-C₆ alkyl-NH-Het, —C₀-C₆ alkyl-NH-C₃-C₇        cycloalkyl, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₆ alkyl-N(C₁-C₄        alkyl)-Het, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₆        alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl,        where x is 0, 1 or 2, or R¹⁴ and R¹⁵, together with the nitrogen        to which they are attached, form a 4-7 membered heterocyclic        ring which optionally contains one or more additional        heteroatoms selected from N, O, and S, wherein said C₁-C₆ alkyl        is optionally substituted by one or more of the substituents        independently selected from the group halo, —OH, —SH, —NH₂,        —NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆        alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl,        —CO₂H, —CO₂(unsubstituted C₁-C₆ alkyl), —CONH₂,        —CONH(unsubstituted C₁-C₆ alkyl), —CON(unsubstituted C₁-C₆        alkyl)(unsubstituted C₁-C₆ alkyl), —SO₃H, —SO₂NH₂,        —SO₂NH(unsubstituted C₁-C₆ alkyl) and —SO₂N(unsubstituted C₁-C₆        alkyl)(unsubstituted C₁-C₆ alkyl);    -   R¹⁶ is C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; and    -   R¹⁷ is H, C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het;    -   or a pharmaceutically acceptable salt or solvate thereof.

Unless otherwise provided, each alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, aryl or Het (including any 3-5-membered, 4-7-membered,5-6-membered or 5-7-membered carbocyclic or heterocyclic rings or ringmoieties) herein is independently unsubstituted or substituted with oneore more substituents defined hereinbelow.

Also included within the scope of this invention are methods forpreparing compounds of this invention, or pharmaceutically acceptablesalts or solvates thereof and methods of using the same. The presentinvention also provides pharmaceutical compositions comprising acompound of this invention, or a pharmaceutically acceptable salt orsolvate thereof.

LXR mediated diseases or conditions include inflammation, cardiovasculardisease and atherosclerosis. Accordingly, the methods of this inventionfurther comprise methods for increasing reverse cholesterol transport,inhibiting cholesterol absorption, and decreasing inflammation. Thepresent invention also provides pharmaceutical compositions comprising acompound of this invention, or a pharmaceutically acceptable salt orsolvate thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “alkyl” represents a straight-or branched-chainsaturated hydrocarbon, containing 1 to 10 carbon atoms, unless otherwiseprovided, which may be unsubstituted or substituted by one or more ofthe substituents described below. Exemplary alkyls include, but are notlimited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, n-pentyl, neopentyl and hexyl and structural isomersthereof. Any “alkyl” herein may be optionally substituted by one or moreof the substituents independently selected from the group halo, —OH,—SH, —NH₂, —NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁ -C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, and—CO₂H.

When combined with another substituent term (e.g., aryl or cycloalkyl asin -alkyl-Ar or -alkyl-cycloalkyl), the “alkyl” term therein refers toan alkylene moiety, that is, an unsubstituted divalent straight-orbranched-chain saturated hydrocarbon moiety, containing 1 to 10 carbonatoms, unless otherwise provided. For example, the term “—C₀-C₆alkyl-Ar”, where C is 1-6 is intended to mean the radical -alkyl-aryl(e.g., —CH₂-aryl or —CH(CH₃)-aryl) and is represented by the bondingarrangement present in a benzyl group. The term “C₀ alkyl” in a moiety,such as —C₀-C₆ alkyl-Ar or —O—(C₀-C₆ alkyl)-Ar, provides for noalkyl/alkylene group being present in the moiety. Thus, when C is zero,—C₀-C₆ alkyl-Ar is equivalent to —Ar and —O—(C₀-C₆ alkyl)-Ar isequivalent to —O—Ar.

As used herein, the term “alkenyl” represents a straight-orbranched-chain hydrocarbon, containing 2 to 10 carbon atoms, unlessotherwise provided, and one or more carbon-carbon double bonds. Alkenylgroups may be unsubstituted or substituted by one or more of thesubstituents described below. Exemplary alkenyls include, but are notlimited ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,isobutenyl, butadienyl, pentenyl and hexenyl and structural isomersthereof. Both cis (Z) and trans (E) isomers of each double bond that maybe present in the compounds of this invention are included within thescope of this invention. Any “alkenyl” herein may be optionallysubstituted by one or more of the substituents independently selectedfrom the group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₆ alkyl),—N(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted—OC₁-C₆ alkyl, and —CO₂H.

As used herein, the term “alkynyl” represents a straight- orbranched-chain hydrocarbon, containing 2 to 10 carbon atoms, unlessotherwise provided, and one or more carbon-carbon triple bonds and,optionally, one or more carbon-carbon double bonds. Both cis (Z) andtrans (E) isomers of each double bond that may be present in thecompounds of this invention are included within the scope of thisinvention. Exemplary alkynyls include, but are not limited ethynyl,propynyl (propargyl, isopropynyl), 1-butynyl, 2-butynyl, 3-butynyl,pentynyl and hexynyl and structural isomers thereof. Any “alkynyl”herein may be optionally substituted by one or more of the substituentsindependently selected from the group halo, —OH, —SH, —NH₂,—NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, and—CO₂H.

For the purposes of this invention, when an alkenyl or alkynyl group isa substituent on an oxygen, nitrogen or sulfur atom (e.g., as in oxy(—OR), thio (—SR), ester (—CO₂R or —C(O)SR), amino (—NRR) or amido(—CONRR) moieties and the like), it is understood that a double ortriple bond of the alkenyl or alkynyl group is not located on carbonsthat are α,β to the oxygen, nitrogen or sulfur atom. Compoundscontaining ene-amino or enol-type moieties (—NR—CR═CR— or —O—CR═CR—) arenot intended to be included within the scope of this invention.

“Cycloalkyl” represents a non-aromatic monocyclic, bicyclic, ortricyclic hydrocarbon containing from 3 to 10 carbon atoms which may beunsubstituted or substituted by one or more of the substituentsdescribed below and may be saturated or partially unsaturated. Exemplarycycloalkyls include monocyclic rings having from 3-7, preferably 3-6,carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl andcycloheptyl. Any “cycloalkyl” herein may be optionally substituted byone or more of the substituents independently selected from the grouphalo, cyano, C₁-C₆ alkyl (which specifically includes C₁-C₆ haloalkyl,—C₀-C₆ alkyl-OH, —C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl,oxo, —OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₁-C₆alkyl-CO₂R′, —C₀-C₆ alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆alkyl-NR′R″, and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″ areindependently selected from H and unsubstituted C₁-C₆ alkyl.

The terms “Ar” or “aryl” as used herein interchangeably at alloccurrences mean a substituted or unsubstituted carbocyclic aromaticgroup, which may be optionally fused to another carbocyclic aromaticgroup moiety or to a cycloalkyl group moiety, which may be optionallysubstituted or unsubstituted. Examples of suitable Ar or aryl groupsinclude phenyl, naphthyl indenyl, 1-oxo-1H-indenyl andtetrahydronaphthyl. Any “Ar”, “aryl” or “phenyl” herein may beoptionally unsubstituted or substituted by one or more of thesubstituents independently selected from the group halo, cyano, C₁-C₆alkyl (which specifically includes C₁-C₆ haloalkyl, —C₀-C₆ alkyl-OH,—C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl, —OC₁-C₆alkyl,—OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆ alkyl-CO₂R′, —C₀-C₆alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆alkyl-C(═NR′)NR′R″, and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″are independently selected from H and unsubstituted C₁-C₆ alkyl.

The term “Het” as used herein means a stable 5- to 7-memberedmonocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to18-membered tricyclic heterocyclic ring group, all of which aresaturated, unsaturated or aromatic, and consist of carbon atoms and fromone to three heteroatoms selected from N, O and S, and which includesbicyclic and tricyclic rings containing one or more fused cycloalkyl,aryl (e.g., phenyl) or heteroaryl (aromatic Het) ring moieties. As usedherein the term “Het” is also intended to encompass heterocyclic groupscontaining nitrogen and/or sulfur where the nitrogen or sulfurheteroatoms are optionally oxidized or the nitrogen heteroatom isoptionally quaternized. The heterocyclic group may be attached at anyheteroatom or carbon atom that results in the creation of a stablestructure. Any “Het” herein may be optionally unsubstituted orsubstituted by one or more of the substituents independently selectedfrom the group halo, cyano, C₁-C₆ alkyl (which specifically includesC₁-C₆ haloalkyl, —C₀-C₆ alkyl-OH, —C₀-C₆ alkyl-SH and —C₀-C₆alkyl-NR′R″), C₃-C₆ alkenyl, oxo, —OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆alkyl-COR′, —C₀-C₆ alkyl-CO₂R′, —C₀-C₆ alkyl-CONR′R″, —OC₀-C₆alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆ alkyl-C(═NR′)NR′R″ and —C₀-C₆alkyl-SO₂NR′R″, wherein each R′ and R” are independently selected from Hand unsubstituted C₁-C₆ alkyl.

Examples of such heterocyclic groups include, but are not limited topiperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepanyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl,pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl,thiazolidinyl, thiazolinyl, thiazolyl, 1,3-benzodioxolyl (e.g.,methylenedioxy-substituted phenyl), 1,4-benzodioxolyl, quinuclidinyl,indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzoxazolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl,dihydrobenzothienyl, dihydroindolyl, tetrazolyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, and oxadiazolyl, as well astriazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyridazinyl, pyrimidinyl and triazinyl which are availableby routine chemical synthesis and are stable.

Examples of the 4-7 membered heterocyclic rings useful in the compoundsof this invention, include, but are not limited to azetidinyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, azepanyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, pyrazinyl,oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl,thiazolidinyl, thiazolinyl, thiazolyl, furyl, pyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, tetrazolyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl, as well as triazolyl,thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyridazinyl, pyrimidinyl and triazinyl which are available by routinechemical synthesis and are stable. The 4-7 membered heterocyclic groupmay be optionally unsubstituted or substituted by one or more of thesubstituents independently selected from the group halo, cyano, C₁-C₆alkyl (which specifically includes C₁-C₆ haloalkyl, —C₀-C₆ alkyl-OH,—C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl, oxo,—OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆ alkyl-CO₂R′,—C₀-C₆ alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆alkyl-C(═NR′)NR′R″ and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″ areindependently selected from H and unsubstituted C₁-C₆ alkyl.

Examples of 5 or 6 membered heterocyclic groups include, but are notlimited to piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, pyridinyl, pyrazinyl, oxazolidinyl,oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl,thiazolinyl, thiazolyl, furyl, pyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, tetrazolyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl, as well as triazolyl,thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyridazinyl, pyrimidinyl and triazinyl which are available by routinechemical synthesis and are stable. The 5-6 membered heterocyclic groupmay be attached at any heteroatom or carbon atom that results in thecreation of a stable structure. The 5-6 membered heterocyclic group maybe optionally unsubstituted or substituted by one or more of thesubstituents independently selected from the group halo, cyano, C₁-C₆alkyl (which specifically includes C₁-C₆ haloalkyl, —C₀-C₆ alkyl-OH,—C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl, oxo,—OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆ alkyl-CO₂R′,—C₀-C₆ alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆alkyl-C(═NR′)NR′R″ and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″ areindependently selected from H and unsubstituted C₁-C₆ alkyl.

In the compounds of this invention, group A is defined as a phenyl orpyridyl fused ring moiety and is exemplified by the following:

Group A fused ring moiety:

The terms “halogen” and “halo” represent chloro, fluoro, bromo or iodosubstituents. “Alkoxy” is intended to mean the radical —OR_(a), whereR_(a) is an alkyl group, wherein alkyl is as defined above, providedthat —O—C₁ alkyl may be optionally substituted by one or more of thesubstituents independently selected from the group halo and —CO₂H.Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like.“Phenoxy” is intended to mean the radical —OR_(ar), where R_(ar) is aphenyl group. “Acetoxy” is intended to mean the radical —O—C(═O)-methyl.“Benzoyloxy” is intended to mean the radical —O—C(═O)-phenyl. “Oxo” isintended to mean the keto diradical ═O, such as present on apyrrolidin-2-one ring.

If a substituent described herein is not compatible with the syntheticmethods of this invention, the substituent may be protected with asuitable protecting group that is stable to the reaction conditions usedin these methods. The protecting group may be removed at a suitablepoint in the reaction sequence of the method to provide a desiredintermediate or target compound. Suitable protecting groups and themethods for protecting and de-protecting different substituents usingsuch suitable protecting groups are well known to those skilled in theart; examples of which may be found in T. Greene and P. Wuts, ProtectingGroups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999),which is incorporated herein by reference in its entirety. In someinstances, a substituent may be specifically selected to be reactiveunder the reaction conditions used in the methods of this invention.Under these circumstances, the reaction conditions convert the selectedsubstituent into another substituent that is either useful as anintermediate compound in the methods of this invention or is a desiredsubstituent in a target compound.

The term “pharmaceutically acceptable salt” is intended to describe asalt that retains the biological effectiveness of the free acid or baseof a specified compound and is not biologically or otherwiseundesirable.

If an inventive compound is a base, a desired salt may be prepared byany suitable method known in the art, including treatment of the freebase with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid,metaphosphoric acid and the like, or with an organic acid, such asacetic acid, trifluoroacetic acid, formic acid, maleic acid, lacticacid, succinic acid, mandelic acid, fumaric acid, malonic acid, malicacid, pyruvic acid, oxalic acid, glycolic acid, citric acid, tartaricacid, gluconic acid, glutaric acid, lactobionic, orotic, cholic, apyranosidyl acid, such as glucuronic acid or galacturonic acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, salicylic acid, cinnamic acid, pamoic acid or1-hydroxy-2-naphthoic acid, a sulfonic acid, such as benzenesulfonicacid, p-toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonicacid, ethanesulfonic acid or the like. Additional examples ofpharmaceutically acceptable salts include sulfates, pyrosulfates,bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides,iodides, acetates, propionates, decanoates, caprylates, acrylates,formates, isobutyrates, caproates, heptanoates, propiolates, oxalates,malonates succinates, suberates, sebacates, fumarates, maleates,butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates,phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates,lactates, γ-hydroxybutyrates, glycollates, tartrates mandelates, andsulfonates, such as xylenesulfonates, methanesulfonates,propanesulfonates, naphthalene-1-sulfonates andnaphthalene-2-sulfonates. Embodiments of a pharmaceutically acceptablesalt (e.g., the hydrochloride salt) of the compounds of this inventionare provided in the Examples.

If an inventive compound is an acid, a desired salt may be prepared byany suitable method known to the art, including treatment of the freeacid with an excess of an inorganic or organic alkaline reagent.Illustrative examples of suitable salts include spalts derived fromammonia; primary, secondary, tertiary amines (including secondary andtertiary cyclic amines), such as ethylene diamine, dicyclohexylamine,ethanolamine, piperidine, morpholine, and piperazine; salts derived fromamino acids such as glycine and arginine; as well as salts derived froman alkali metal, alkaline earth metal, or ammonium hydroxide, carbonate,alkoxide or sulfate, such as sodium hydroxide, sodium carbonate, sodiumbicarbonate, sodium sulfate, etc., and corresponding alkaline saltscontaining, for example, Li⁺, K⁺, Ca⁺⁺, Mg⁺⁺ and NH₄ ⁺ cations.

Because the compounds of this invention may contain both acid and basemoieties, pharmaceutically acceptable salts may be prepared by treatingthese compounds with an alkaline reagent or an acid reagent,respectively. Accordingly, this invention also provides for theconversion of one pharmaceutically acceptable salt of a compound of thisinvention, e.g., a hydrochloride salt, into another pharmaceuticallyacceptable salt of a compound of this invention, e.g., a mesylate saltor a sodium salt.

The term “solvate” is intended to mean a pharmaceutically acceptablesolvate form of a specified compound of this invention, or a saltthereof, that retains the biological effectiveness of such compound.Examples of solvates include compounds of the invention in combinationwith water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, aceticacid, or ethanolamine. In the case of compounds, salts, or solvates thatare solids, it is understood by those skilled in the art that theinventive compounds, salts, or solvates may exist in different crystalforms, all of which are intended to be within the scope of the presentinvention and specified formulas.

Also included within the scope of this invention are prodrugs of thecompounds of this invention. The ester compounds of this invention,wherein X is other than —OH, may be considered prodrugs. Such estercompounds may be converted to compounds that are active as LXRmodulators and may be, themselves, active as LXR modulators. The term“prodrug” is intended to mean a compound that is converted underphysiological conditions, e.g., by solvolysis or metabolically, to acompound according to this invention that is pharmaceutically active. Aprodrug may be a derivative of one of the compounds of this inventionthat contains a carboxylic or phosphoric acid ester or amide moiety thatmay be cleaved under physiological conditions. A prodrug containing sucha moiety may be prepared according to conventional procedures, forexample, by treatment of a compound of this invention containing anamino, amido or hydroxyl moiety with a suitable derivatizing agent, forexample, a carboxylic or phosphoric acid halide or acid anhydride, or byconverting a carboxyl moiety of a compound of this invention to an esteror amide. Prodrugs of the compounds of this invention may be determinedusing techniques known in the art, for example, through metabolicstudies. See, e.g., “Design of Prodrugs,” (H. Bundgaard, Ed.) 1985,Elsevier Publishers B. V., Amsterdam, The Netherlands.

It will be appreciated by those skilled in the art that the compounds ofthis invention may exist in different tautomeric forms. All tautomericforms of the compounds described herein are intended to be encompassedwithin the scope of the present invention.

The compounds of this invention may contain at least one chiral centerand may exist as single stereoisomers (e.g., single enantiomers),mixtures of stereoisomers (e.g., any mixture of enantiomers ordiastereomers) or racemic mixtures thereof. All such singlestereoisomers, mixtures and racemates are intended to be encompassedwithin the broad scope of the present invention. Compounds identifiedherein as single stereoisomers are meant to describe compounds that arepresent in a form that are at least 90% enantiomerically pure. Where thestereochemistry of the chiral carbons present in the chemical structuresillustrated herein is not specified, the chemical structure is intendedto encompass compounds containing either stereoisomer of each chiralcenter present in the compound. Such compounds may be obtainedsynthetically, according to the procedures described herein usingoptically pure (enantiomerically pure) or substantially optically purematerials. Alternatively, these compounds may be obtained byresolution/separation of a mixture of stereoisomers, including racemicmixtures, using conventional procedures. Exemplary methods that may beuseful for the resolution/separation of mixtures of stereoisomersinclude chromatography and crystallization/re-crystallization. Otheruseful methods may be found in “Enantiomers, Racemates, and Resolutions,“J. Jacques et al., 1981, John Wiley and Sons, New York, N.Y., thedisclosure of which is incorporated herein by reference.

In one embodiment of this invention, the group U—(CR¹R²)_(p)— is locatedon the A-ring moiety in a position that is meta or para to the—Y—(CR⁴R⁵)_(n)— moiety. Preferably, the group U—(CR¹R²)_(p)— is locatedin a position that is meta to the —Y—(CR⁴R⁵)_(n)— moiety.

In another embodiment, this invention is directed to a compound ofFormula II:

wherein:

-   -   X is CH or N;    -   Y is O, or S;    -   U is selected from halo, —OR¹⁰, —NR¹⁴R¹⁵, cyano, —COOR¹⁰,        —OCOR¹³, —CONR¹⁴R¹⁵, —N(R¹⁴)COR¹³, —SO₂NR¹⁴R¹⁵, —C(═NH)NR¹⁴R¹⁵,        and a 5 or 6-membered heterocyclic group;    -   A is a phenyl fused ring moiety, wherein k is 0 or 1;    -   W¹ is selected from C₃-C₈ cycloalkyl, aryl and Het, wherein said        C₃-C₈ cycloalkyl, Ar and Het are optionally unsubstituted or        substituted with one or more groups independently selected from        halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,        —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰, —C₀-C₄        alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄ alkyl-NR¹¹R¹²,        —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SO₃H, —C₀-C₄        alkyl-SO₂NR¹¹R¹², —C₀-C₄ alkyl-SO₂R¹⁰, —C₀-C₄ alkyl-SOR¹³,        —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄ alkyl-OC(O)NR¹¹R¹², —C₀-C₄        alkyl-OC(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)OR¹³, —C₀-C₄        alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄ alkyl-NR¹¹COR¹³, where said        C₁-C₆ alkyl is optionally unsubstituted or substituted by one or        more halo substituents;    -   W² is selected from H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄        alkyl-OR¹⁰, —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰, —C₀-C₄        alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄        alkyl-OCONR¹¹R¹², —C₀-C₄ alkyl-NR¹¹CONR¹¹R¹², —C₀-C₄        alkyl-NR¹¹COR¹³, —C₀-C₄ alkyl-Het, —C₀-C₄ alkyl-Ar and —C₀-C₄        alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents,        and wherein the C₃-C₇ cycloalkyl, Ar and Het moieties of said        —C₀-C₄ alkyl-Het, —C₀-C₄ alkyl-Ar and —C₀-C₄ alkyl-C₃-C₇        cycloalkyl are optionally unsubstituted or substituted with one        or more groups independently selected from halo, cyano, nitro,        C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-CO₂R¹⁰,        —C₀-C₄ alkyl-C(O)SR¹⁰, —C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄        alkyl-COR¹³, —C₀-C₄ alkyl-N¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄        alkyl-OR¹⁰, —C₀-C₄ alkyl-SO₃H, —C₀-C₄ alkyl-SO₂NR¹¹R¹², —C₀-C₄        alkyl-SO₂R¹⁰, —C₀-C₄ alkyl-SOR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄        alkyl-OC(O)NR¹¹R¹², —C₀-C₄ alkyl-OC(O)OR¹³, —C₀-C₄        alkyl-NR¹¹C(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄        alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents;    -   W³is selected from the group consisting of: H, halo, C₁-C₆        alkyl, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄        alkyl-OR¹⁰, —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰, —C₀-C₄        alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄        alkyl-OCONR¹¹R¹², —C₀-C₄ alkyl-NR¹¹CONR¹¹R¹², —C₀-C₄        alkyl-NR¹¹COR¹³, —C₀-C₄ alkyl-Het, —C₁-C₄ alkyl-Ar and —C₁-C₄        alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents;    -   Q is Ar or Het; wherein said Ar and Het are optionally        unsubstituted or substituted with one or more groups        independently selected from halo, cyano, nitro, C₁-C₆ alkyl,        C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄        alkyl-C(O)SR¹⁰, —C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³,        —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰,        —C₀-C₄ alkyl-SO₃H, —C₀-C₄ alkyl-SO₂NR¹¹R¹², —C₀-C₄ alkyl-SO₂R¹⁰,        —C₀-C₄ alkyl-SOR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄        alkyl-OC(O)NR¹¹R¹², —C₀-C₄ alkyl-OC(O)OR¹³, —C₀-C₄        alkyl-NR¹¹C(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄        alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents,    -   p is 0-4;    -   n is 3;    -   m is 0 or 1;    -   q is 0 or 1;    -   t is 0;    -   each R¹ and R² are independently selected from H, fluoro, C₁-C₆        alkyl, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SR¹⁰, —C₁-C₄ alkyl-Het,        —C₁-C₄ alkyl-Ar and —C₁-C₄ alkyl-C₃-C₇ cycloalkyl, where said        C₁-C₆ alkyl is optionally unsubstituted or substituted by one or        more halo substituents;    -   each R³ is the same or different and is independently selected        from halo, cyano, C₁-C₆ alkyl, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄        alkyl-OR¹⁰, —C₀-C₄ alkyl-SO₂NR¹¹R¹², and —C₀-C₄ alkyl-CO₂H,        wherein said C₁-C₆ alkyl is optionally unsubstituted or        substituted by one or more halo substituents;    -   each R⁴ and R⁵ is independently selected from H, fluoro and        C₁-C₆ alkyl;    -   R⁶ and R⁷ are each independently selected from H, fluoro and        C₁-C₆ alkyl;    -   R⁸ and R⁹ are each independently selected from H, fluoro and        C₁-C₆ alkyl;    -   R¹⁰ is selected from H, C₁-C₆ alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄        alkyl-Het and —C₀-C₄ alkyl-C₃-C₇ cycloalkyl;    -   each R¹¹ and each R¹² are independently selected from H, C₁-C₆        alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het and —C₀-C₄ alkyl-C₃-C₇        cycloalkyl, or R¹¹ and R¹² together with the nitrogen to which        they are attached form a 4-7 membered heterocyclic ring which        optionally contains one or more additional heteroatoms selected        from N, O, and S;    -   R¹³ is selected from C₁-C₆ alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄        alkyl-Het and —C₀-C₄ alkyl-C₃-C₇ cycloalkyl;    -   R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆ alkyl,        C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het,        —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-O—Ar, —C₀-C₄        alkyl-O-Het, —C₀-C₄ alkyl-O-C₃-C₇ cycloalkyl, —C₀-C₄        alkyl-S(O)_(x)-C₁-C₆ alkyl, —C₀-C₄ alkyl-S(O)_(x)—Ar, —C₀-C₄        alkyl-S(O)_(x)-Het, —C₀-C₄ alkyl-S(O)_(x)-C₃-C₇ cycloalkyl,        —C₀-C₄ alkyl-NH—Ar, —C₀-C₄ alkyl-NH-Het, —C₀-C₄ alkyl-NH—C₃-C₇        cycloalkyl, —C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₄ alkyl-N(C₁-C₄        alkyl)-Het, —C₀-C₄ alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₄        alkyl-Ar, —C₀-C₄ alkyl-Het and —C₀-C₄ alkyl-C₃-C₇ cycloalkyl,        where x is 0, 1 or 2, or R¹⁴ and R¹⁵, together with the nitrogen        to which they are attached, form a 4-7 membered heterocyclic        ring which optionally contains one or more additional        heteroatoms selected from N, O, and S, wherein said C₁-C₆ alkyl,        C₃-C₆ alkenyl, C₃-C₆ alkynyl are optionally substituted by one        or more of the substituents independently selected from the        group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₄ alkyl),        —N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl),        unsubstituted —OC₁-C₄ alkyl, —CO₂H, —CO₂(unsubstituted C₁-C₄        alkyl), —CONH₂, —CONH(unsubstituted C₁-C₄ alkyl),        —CON(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl),        —SO₃H, —SO₂NH₂, —SO₂NH(unsubstituted C₁-C₄ alkyl) and        —SO₂N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl);    -   or a pharmaceutically acceptable salt or solvate thereof.

Unless otherwise provided, each alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, aryl or Het herein is independently unsubstituted orsubstituted with one ore more substituents defined hereinabove.

The LXR modulating agents of this invention may contain the variety of Ugroups defined above. In one embodiment of this invention, U is selectedfrom halo, —OR¹⁰, —NR¹¹R¹², cyano, —COOR¹⁰, —OCOR¹³, —SO₂NR¹⁴R¹⁵,—C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁴)COR¹⁶ and a 5 or 6-membered heterocyclic group.In another embodiment, U is selected from halo, OR¹⁰, —COOR¹⁰,—CONR¹¹R¹², —SO₂NR¹¹R¹², —C(═NH)NR¹¹R¹², and a 5 or 6-memberedheterocyclic group. In other embodiments, U is halo, —OR¹⁰, —COOR¹⁰,—CONR¹¹R¹², —NR¹¹R¹², or a 5 or 6-membered heterocyclic group morespecifically, U is —OR¹⁰, —COOR¹⁰, —CONR¹¹R¹² or —NR¹¹R¹². For example,U may be selected from bromo, —OH, —COOH, —COOCH₃, —CONH₂, —COOCH₃,—CON(H)CH₂-furan-2-yl, —N(H)CH₂-furan-2-yl,triazolyl triazolyl andtetrazolyl. In specific embodiments of the compounds of this invention,U is —OH, —COOH, —CONH₂, —CON(H)CH₂-furan-2-yl, or —N(H)CH₂-furan-2-yl.

In specific embodiments, the compounds of this invention are definedwherein p is 0-3. In preferred embodiments, p is 0, 1 or 2. In specificembodiments of this invention, p is 1 or 2.

In other embodiments, each R¹ and R² are independently selected from H,C₁-C₄ alkyl and —C₀-C₄ alkyl-OR¹¹. By virtue of the definitions givenabove for the term “alkyl”, this definition of R³ also encompasses alkylgroups that are optionally substituted with the substituents specifiedin the definitions above. Accordingly, in the compounds and methods ofthis invention, each R¹ and R² may be independently selected from H,C₁-C₄ alkyl, —OH, —C₁-C₄ alkyl-OH, —C₁-C₄ alkyl-NH₂, —C₁-C₄alkyl-NH(C₁-C₄ alkyl), and —C₁-C₄ alkyl-N(C₁-C₄ alkyl)(C₁-C₄ alkyl). Ina specific embodiment of the compounds of this invention, R¹ and R² areH.

The group

describes a 6-membered aromatic ring, specifically, a phenyl or pyridylring, which may be unsubstituted (k=0) or substituted by one or moresubstituents R³. In a preferred embodiment, the compounds of thisinvention are defined where the A group is a phenyl fused ring moiety.The total number of R³ substituents that may be present in a compound ofthis invention is represented by “k”. When A is a phenyl fused ringmoiety, k is 0-3, meaning that there can be up to three R³ substituentson the 6-membered aromatic ring. When A is a pyridyl fused ring moiety,k is 0-2, meaning that there can be up to two R³ substituents on the6-membered aromatic ring. In this embodiment, R³ is not attached to theN atom of the pyridyl ring moiety ring. Preferably, k is 0 or 1. Inspecific embodiments, k is 0.

In the embodiments wherein k is 1 or more, each R³ may be the same ordifferent and may be independently selected from halo, C₁-C₄ alkyl andC₁-C₄ alkoxy. By virtue of the definitions given above for the term“alkyl”, this definition of R³ also encompasses alkyl groups that areoptionally substituted with the substituents specified in thedefinitions above.

When the moiety —Y(CR⁴R⁵)_(n)— is substituted and R⁴ and R⁵ aredifferent on at least one (CR⁴R⁵) moiety (e.g., when one of R⁴ or R⁵ ismethyl and the other of R⁴ and R⁵ is hydrogen) a chiral compound isobtained. All single stereoisomers, mixtures and racemates of thesechiral compounds are intended to be encompassed within the broad scopeof the present invention.

In another embodiment, the compounds of this invention of this inventionare defined wherein n is 2-4. In specific embodiments, n is 3.

In the compounds of this invention, t may be 0 or 1. When t is 1, thecompound of this invention is the N-oxide of the tertiary amine, havingthe formula:

When t is 0, the compound of this invention is the tertiary amine havingthe formula:

In specific embodiments of the compounds this invention, q is 1 and R⁸and R⁹ are both H.

Group Q is selected from C₃-C₇ cycloalkyl, aryl and Het. By virtue ofthe definitions given above for the terms “cycloalkyl”, “aryl” and“Het”, this definition of Q also encompasses cycloalkyl, aryl and Hetgroups that are optionally substituted from 1 to 4 times, morepreferably, from 1 to 3 times. In one embodiment, Q is an aryl group ora Het group. In specific non-limiting embodiments, Q is a substitutedphenyl group, containing one or two substituents selected from halo,C₁-C₄ alkoxy; and C₁-C₄ alkyl (specifically including C₁-C₄ haloalkyl)or Q is a 1,3-benzodioxolyl or dihydrobenzofuranyl group. Morespecifically, Q is a phenyl group substituted by one or two substituentsselected from chloro, trifluoromethyl and methoxy or is a1,3-benzodioxolyl or a dihydrobenzofuranyl group. Specifically, in thecompounds of this invention, Q is 2-chloro-3-trifluoromethylphenyl,4-methoxyphenyl, 2,4-dimethoxyphenyl, benzo[1,3]dioxol-5-yl, or(2,3-dihydro)benzofuran-5-yl.

In one embodiment of the compounds of this invention, m is 0 or 1 and R⁶and R⁷ are independently selected from H and C₁-C₄ alkyl. In anotherembodiment, W³ is H. In yet another embodiment, W¹ and W² are the sameor different and are selected from C₃-C₆ cycloalkyl, aryl and Het. Inanother embodiment, m is 1, R⁶ and R⁷ are both H, W³ is H, W¹ isselected from C₃-C₆ cycloalkyl, aryl and Het and W² is selected from—CO₂R¹⁰, —NR¹¹R¹², —CONR¹¹R¹², —OCOR¹³, —OCONR¹¹R¹², C₁-C₄ alkyl, —C₀-C₄alkyl-OR¹⁰, —C₁-C₄ alkyl-Het, —C₁-C₄ alkyl-Ar and —C₁-C₄ alkyl-C₃-C₆cycloalkyl. In other embodiments of the compounds of this invention, mis 0 or m is 1 and R⁶ and R⁷ are both H, W¹ is selected from C₃-C₆cycloalkyl, aryl and Het and W² and W³ are each H. By virtue of thedefinitions given above, for the terms “alkyl”, “cycloalkyl”, “aryl” and“Het”, W¹ and W² also encompasses the foregoing groups optionallysubstituted with the substituents specified in the definitions above. Inone embodiment, W¹ and/or W² may be phenyl, thienyl, pyridyl, furanyl,pyrrolyl, morpholinyl, or pyrrolidinyl, where each phenyl, thienyl,pyridyl, furanyl, pyrrolyl, morpholinyl, or pyrrolidinyl may beoptionally substituted from 1 to 3 times, more preferably from 1 to 2times with one or more of the substituents defined hereinabove. Forexample, W¹ and/or W² may be independently substituted by one or moresubstituents independently selected from C₁-C₄ alkyl, —OH, halo,—O—C₁-C₄ alkyl, and —C₁-C₄ haloalkyl. In another embodiment, W¹ may bephenyl, thienyl, pyridyl, furanyl, pyrrolyl, morpholinyl, orpyrrolidinyl and W² may be phenyl, thienyl, pyridyl, furanyl, pyrrolyl,morpholinyl, pyrrolidinyl, cyclohexyl, cyclopentyl, C₁-C₄ alkyl (such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl andsecbutyl) or C₁-C₄ haloalkyl, where each phenyl, thienyl, pyridyl,furanyl, pyrrolyl, morpholinyl, or pyrrolidinyl may be optionallyindependently substituted with 1, 2 or 3 substituents independentlyselected from C₁-C₄ alkyl, —OH, halo, —O—C₁-C₄ alkyl, and —C₁-C₄haloalkyl.

In specific embodiments of this invention, m is 1 and R⁶ and R⁷ are bothH, W¹ is aryl and W² is aryl or C₁-C₄ alkyl. In more specificembodiments, m is 1 and R⁶ and R⁷ are both H, W³ is H, W¹ and W² areeach unsubstituted phenyl or W¹ is unsubstituted phenyl and W² ismethyl.

In other embodiments of this invention, the —C₀-C₆ alkyl- and —C₀-C₄alkyl-moieties of the substitutents defined herein are unsubstituted—C₀-C₆ alkyl- and unsubstituted —C₀-C₄ alkyl- moieties, respectively.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.

Specific embodiments of this invention comprise compounds of Formula Iand Formula II wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each H;U is —OR¹⁰, —COOR¹⁰, —CONR¹¹R¹² or —NR¹¹R¹²; A is a phenyl fused ring; Qis a substituted phenyl group containing one or two substituentsselected from halo, C₁-C₄ alkoxy and C₁-C₄ alkyl or Q is a1,3-benzodioxolyl or a dihydrobenzofuranyl group; p is 1 or 2; n is 3; mis 1; q is 1; k is 0; t is 0; W¹ is aryl; W² is aryl or C₁-C₄ alkyl; andW³ is H; or a pharmaceutically acceptable salt or solvate thereof.

More specific embodiments of this invention comprise compounds ofFormula I and Formula II wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ andW³ are each H; U is —OH, —COOH, —CONH₂, —CON(H)CH₂-furan-2-yl, or—N(H)CH₂-furan-2-yl; A is a phenyl fused ring; Q is a phenyl groupsubstituted by one or two substituents selected from chloro,trifluoromethyl and methoxy or Q is a 1,3-benzodioxolyl or adihydrobenzofuranyl group; p is 1 or 2; n is 3; m is 1; q is 1; k is 0;t is 0; W¹ is unsubstituted phenyl; and W² is methyl or unsubstitutedphenyl; or a pharmaceutically acceptable salt or solvate thereof.

Compounds of this invention include:

-   -   2-[2-{[2-chloro-3(trifluoromethyl)-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran        acetic acid,    -   2-[2-([2,4-dimethoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran        acetic acid,    -   2-[2-{[(2,3-methylenedioxy)benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran        acetic acid,    -   2-[2[(2,3-dihydrobenzo[b]furan)methyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran        acetic acid,    -   2-[2-{[4-methoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran        acetic acid,    -   (R)-2-[2-{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuran        acetic acid,    -   (R)-2-[2-{([(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuran        acetic acid,    -   (S)-2-[2-[{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-benzofuran        acetic acid,    -   (S)-2-[2[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuran        acetic acid,    -   2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuran        acetic acid,    -   2-[2-{[(2,3-methylenedioxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuran        acetic acid,    -   2-[2-{[(2,4-dimethoxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuran        acetic acid,    -   2-{2-[(4-methoxy-benzyl)(2,2-diphenylethyl)amino]-ethyl}-6-benzofuran        acetic acid,    -   2-{2-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl-amino]ethyl}-benzofuran-6-yl)-N-furan-2-yl        methyl-acetamide,    -   2-{2-[(2,4-dimethoxy-benzyl)(2,2-diphenylethyl)-amino]ethyl}-benzofuran-6-yl)-N-furan-2-yl        methyl-acetamide,    -   2-{2-[(2(chloro-3-(trifluoromethyl)-benzyl)(2,2-diphenylethyl-amino]ethyl}-benzofuran-6-yl)-acetamide,    -   (racemic)2-{3-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2-phenyl-propyl)-amino]-propyl}-benzofuran-6-yl)-acetic        acid,    -   2-(2-{3-[(2-chloro-3-(trifluoromethyl)-benzyl-(2,2-diphenylethyl)-amino]-propyl}-benzofuran-6-yl)-ethanol,    -   2-(2-{3-[(2,4-dimethoxy)-benzyl-(2,2-diphenylethyl)-amino]-propyl}-benzofuran-6-yl)-ethanol,    -   2-{3-[(2-chloro-3-(trifluoromethyl)-benzyl)-((R)-2-phenyl-propyl)-amino]-propyl}-benzofuran-6-yl)-acetic        acid,    -   2-{3-[(2-chloro-3-(trifluoromethyl)-benzyl)-((S)-2-phenyl-propyl)-amino]-propyl}-benzofuran-6-yl)-acetic        acid,    -   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-{2-[(furan-2-ylmethyl)-amino]-ethyl-benzofuran-2-yl)-propyl]-amine,    -   and a stereoisomer, a stereoisomeric mixture or racemate thereof        and a pharmaceutically acceptable salt or solvate thereof.

Preferred compounds of this invention include:

-   -   2-[2-{[2,4-dimethoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran        acetic acid,    -   (R)-2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuran        acetic acid,    -   2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuran        acetic acid,    -   2-[2-{[(2,4dimethoxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuran        acetic acid,    -   and a stereoisomer, a stereoisomeric mixture or racemate thereof        and a pharmaceutically acceptable salt or solvate thereof.

As used herein, the term “LXR agonist” refers to compounds which achieveat least 20% activation of LXR relative to 24(S),25-epoxycholesterol,the appropriate positive control in the HTRF assay described below inTest Method 1. It should be noted that to show activity in the specificTest Methods described herein, the LXR modulator compound must bind tothe LXR nuclear receptor and recruit the specific peptide derived fromthe coactivator protein, SRC1, to the modulator compound-bound LXRcomplex. The compounds of this invention that form an LXR-modulatorcompound complex and recruit SRC1, may also recruit at least one or moreof the other >80 known different nuclear receptor cofactors. Recruiterpeptides derived from any of these other nuclear receptor cofactors maybe similarly prepared and assayed according to known procedures.

The compounds of this invention are useful for a variety of medicinalpurposes. The compounds of this invention may be used in methods for theprevention or treatment of LXR mediated diseases and conditions. Thisinvention further provides compounds of this invention for use in thepreparation of a medicament for the prevention or treatment of an LXRmediated disease or condition. LXR mediated diseases or conditionsinclude inflammation, cardiovascular disease including atherosclerosis,arteriosclerosis, hypercholesteremia, and hyperlipidemia. In particular,the compounds of this invention are useful in the treatment andprevention of inflammation, cardiovascular disease includingatherosclerosis and hypercholesteremia.

The present invention also provides a method for increasing reversecholesterol transport, compounds of this invention for increasingreverse cholesterol transport and the use of compounds of this inventionfor the preparation of a medicament for increasing reverse cholesteroltransport. Lipoprotein metabolism is a dynamic process comprised ofproduction of triglyceride rich particles from the liver (as VLDL),modification of these lipoprotein particles within the plasma (VLDL toIDL to LDL) and clearance of the particles from the plasma, again by theliver. This process provides the transport of triglycerides and freecholesterol to cells of the body. Reverse cholesterol transport is theproposed mechanism by which peripheral cholesterol is returned to theliver from extra-hepatic tissue. The process is carried out by HDLcholesterol. The combination of lipoprotein production (VLDL, HDL) fromthe liver, modification of particles (all) within the plasma andsubsequent clearance back to the liver, accounts for the steady statecholesterol concentration of the plasma. Without wishing to be bound byany particular theory, it is currently believed that the compounds ofthis invention increase reverse cholesterol transport by increasingcholesterol efflux from the arteries.

Additionally, this invention provides a method for inhibitingcholesterol absorption, compounds of this invention for inhibitingcholesterol absorption and the use of compounds of this invention forthe preparation of a medicament for inhibiting cholesterol absorption.This invention also provides a method for increasing reverse cholesteroltransport, compounds of this invention for increasing reversecholesterol transport and the use of compounds of this invention for thepreparation of a medicament for increasing reverse cholesteroltransport.

The compounds of this invention may also be useful for the prevention ortreatment of inflammation and neurodegenerative diseases or neurologicaldisorders. Accordingly, this invention also provides a method forpreventing or treating inflammation (See A. J. Fowler et al., J. Invest.Dermatol., 2003 February, 120 (2): 246-255 and S. B. Joseph, et al. Nat.Med., Feb. 9, 2003 (2): 213-219) and a method for preventing or treatingneurodegenerative diseases or neurological disorders, particularlyneurodegenerative diseases or disorders characterized by neurondegeneration, neuron injury or impaired plasticity or inflammation inthe CNS (as disclosed in U.S. Provisional Patent Application No.60/368,424, filed 27 March, 2002). Particular diseases or conditionsthat are characterized by neuron degeneration and inflammation, and thusbenefiting from the growth and/or repair of neurons include stroke,Alzheimer's disease, fronto-temporal dementias (tauopathies), peripheralneuropathy, Parkinson's disease, dementia with Lewy bodies, Huntington'sdisease, amyotrophic lateral sclerosis and multiple sclerosis. Diseasesor conditions that are characterized by neuron degeneration and/orimpaired plasticity include psychiatric disorders such as schizophreniaand depression. Particular diseases or conditions that are characterizedby neuronal injury include those conditions associated with brain and/orspinal cord injury, including trauma.

The methods of the present invention are useful for the treatment ofanimals including mammals generally and particularly humans. The presentinvention further provides the use of compounds of this invention forthe preparation of a medicament for increasing reverse cholesteroltransport.

The methods of the present invention comprise the step of administeringa therapeutically effective amount of the compound of this invention. Asused herein, the term “therapeutically effective amount” refers to anamount of the compound of this invention that is sufficient to achievethe stated effect. Accordingly, a therapeutically effective amount of acompound of this invention used in the method for the prevention ortreatment of LXR mediated diseases or conditions will be an amountsufficient to prevent or treat the LXR mediated disease or condition.Similarly, a therapeutically effective amount of a compound of thisinvention for use in the method of increasing reverse cholesteroltransport will be an amount sufficient to increase reverse cholesteroltransport.

The amount of a compound of this invention or pharmaceuticallyacceptable salt or solvate thereof, which is required to achieve thedesired biological effect will depend on a number of factors such as theuse for which it is intended, the means of administration, and therecipient, and will be ultimately at the discretion of the attendantphysician or veterinarian. In general, a typical daily dose for thetreatment of LXR mediated diseases and conditions in a human, forinstance, may be expected to lie in the range of from about 0.01 mg/kgto about 100 mg/kg. This dose may be administered as a single unit doseor as several separate unit doses or as a continuous infusion. Similardosages would be applicable for the treatment of other diseases,conditions and therapies including increasing reverse cholesteroltransport, and inhibiting cholesterol absorption.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising a compound of this invention or apharmaceutically acceptable salt or solvate thereof, as the activeingredient, and at least one pharmaceutical carrier or diluent. Thesepharmaceutical compositions may be used in the prophylaxis and treatmentof the foregoing diseases or conditions and in cardiovascular therapiesas mentioned above. The carrier must be pharmaceutically acceptable andmust be compatible with, i.e. not have a deleterious effect upon, theother ingredients in the composition. The carrier may be a solid orliquid and is preferably formulated as a unit dose formulation, forexample, a tablet which may contain from 0.05 to 95% by weight of theactive ingredient.

Possible formulations include those suitable for oral, sublingual,buccal, parenteral (for example subcutaneous, intramuscular, orintravenous), rectal, topical including transdermal, intranasal andinhalation administration. Most suitable means of administration for aparticular patient will depend on the nature and severity of the diseaseor condition being treated or the nature of the therapy being used andon the nature of the active compound, but where possible, oraladministration is preferred for the prevention and treatment of LXRmediated diseases and conditions.

Formulations suitable for oral administration may be provided asdiscrete units, such as tablets, capsules, cachets, lozenges, eachcontaining a predetermined amount of the active compound; as powders orgranules; as solutions or suspensions in aqueous or non-aqueous liquids;or as oil-in-water or water-in-oil emulsions.

Formulations suitable for sublingual or buccal administration includelozenges comprising the active compound and, typically a flavored base,such as sugar and acacia or tragacanth and pastiles comprising theactive compound in an inert base, such as gelatin and glycerine orsucrose acacia.

Formulations suitable for parenteral administration typically comprisesterile aqueous solutions containing a predetermined concentration ofthe active compound; the solution is preferably isotonic with the bloodof the intended recipient. Additional formulations suitable forparenteral administration include formulations containingphysiologically suitable co-solvents and/or complexing agents such assurfactants and cyclodextrins. Oil-in-water emulsions are also suitableformulations for parenteral formulations. Although such solutions arepreferably administered intravenously, they may also be administered bysubcutaneous or intramuscular injection.

Formulations suitable for rectal administration are preferably providedas unit-dose suppositories comprising the active ingredient in one ormore solid carriers forming the suppository base, for example, cocoabutter.

Formulations suitable for topical or intranasal application includeointments, creams, lotions, pastes, gels, sprays, aerosols and oils.Suitable carriers for such formulations include petroleum jelly,lanolin, polyethyleneglycols, alcohols, and combinations thereof.

Formulations of the invention may be prepared by any suitable method,typically by uniformly and intimately admixing the active compound withliquids or finely divided solid carriers or both, in the requiredproportions and then, if necessary, shaping the resulting mixture intothe desired shape.

For example a tablet may be prepared by compressing an intimate mixturecomprising a powder or granules of the active ingredient and one or moreoptional ingredients, such as a binder, lubricant, inert diluent, orsurface active dispersing agent, or by molding an intimate mixture ofpowdered active ingredient and inert liquid diluent.

Suitable formulations for administration by inhalation include fineparticle dusts or mists which may be generated by means of various typesof metered dose pressurized aerosols, nebulisers, or insulators.

For pulmonary administration via the mouth, the particle size of thepowder or droplets is typically in the range 0.5-10 μM, preferably 1-5μM, to ensure delivery into the bronchial tree. For nasaladministration, a particle size in the range 10-500 μM is preferred toensure retention in the nasal cavity.

Metered dose inhalers are pressurized aerosol dispensers, typicallycontaining a susperision or solution formulation of the activeingredient in a liquefied propellant. During use, these devicesdischarge the formulation through a valve adapted to deliver a meteredvolume, typically from 10 to 150 μL, to produce a fine particle spraycontaining the active ingredient. Suitable propellants include certainchlorofluorocarbon compounds, for example, dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof.The formulation may additionally contain one or more co-solvents, forexample, ethanol surfactants, such as oleic acid or sorbitan trioleate,anti-oxidants and suitable flavoring agents. Nebulisers are commerciallyavailable devices that transform solutions or suspensions of the activeingredient into a therapeutic aerosol mist either by means ofacceleration of a compressed gas typically air or oxygen, through anarrow venturi orifice, or by means of ultrasonic agitation. Suitableformulations for use in nebulisers consist of the active ingredient in aliquid carrier and comprising up to 40% w/w of the formulation,preferably less than 20% w/w. The carrier is typically water or a diluteaqueous alcoholic solution, preferably made isotonic with body fluids bythe addition of, for example, sodium chloride. Optional additivesinclude preservatives if the formulation is not prepared sterile, forexample, methyl hydroxy-benzoate, anti-oxidants, flavoring agents,volatile oils, buffering agents and surfactants.

Suitable formulations for administration by insufflation include finelycomminuted powders which may be delivered by means of an insufflator ortaken into the nasal cavity in the manner of a snuff. In theinsufflator, the powder is contained in capsules or cartridges,typically made of gelatin or plastic, which are either pierced or openedin situ and the powder delivered by air drawn through the device uponinhalation or by means of a manually-operated pump. The powder employedin the insufflator consists either solely of the active ingredient or ofa powder blend comprising the active ingredient, a suitable powderdiluent, such as lactose, and an optional surfactant. The activeingredient typically comprises from 0.1 to 100 w/w of the formulation.

In addition to the ingredients specifically mentioned above, theformulations of the present invention may include other agents known tothose skilled in the art of pharmacy, having regard for the type offormulation in issue. For example, formulations suitable for oraladministration may include flavoring agents and formulations suitablefor intranasal administration may include perfumes.

General Methods

In one embodiment of this invention, the method for the preparation ofcompounds of Formulas I or II comprises the steps of:

-   -   (a) coupling an acetylene having the formula: with a phenol        having the formula:        where Halo is a halogen selected from iodo and bromo, in the        presence of a metal catalyst to form an aryl-alcohol having the        formula:    -   (b) converting alcohol moiety of the aryl-alcohol formed in        step (a) into L′, where L′ is a leaving group such as a halogen        (iodide, bromide or chloride), sulfonate (tosylate, mesylate,        triflate, etc.) or is a group that is converted to a leaving        group (e.g., an alcohol), and treating the resulting compound        with an amine having the formula:        to form the compound of Formula I or Formula II, respectively;    -   (c) optionally converting the compound of Formula I or Formula        II from step (b) into another compound of Formula I or Formula        II, respectively; and    -   (d) optionally oxidizing the compound formed in step (c) to the        N-oxide thereof.

In another embodiment of this invention, the method for the preparationof compounds of Formulas I or II comprises the steps of:

-   -   (a) coupling an acetylene having the formula: with a phenol        having the formula:        where Halo is a halogen selected from iodo and bromo, in the        presence of a metal catalyst to form an aryl-alcohol having the        formula:    -   (b) converting alcohol moiety of the aryl-alcohol formed in        step (a) into L′, where L′ is a leaving group such as a halogen        (iodide, bromide or chloride) or a sulfonate (tosylate,        mesylate, triflate, etc.) and treating the resulting compound        with sodium azide, followed by hydrogenation in the presence of        a palladium catalyst to form a primary amine having the formula:    -   (c) treating the primary amine with a first aldehyde in the        presence of a reducing agent, to form a secondary amine and        treating the secondary amine with a second        aldehyde in the presence of a reducing agent to form the        compound of Formula I or Formula II, respectively,    -   (d) optionally converting the compound of Formula I or Formula        II from step (b) into another compound of Formula I or Formula        II, respectively; and    -   (e) optionally oxidizing the compound formed in step (b) or (c)        to the N-oxide thereof.        Specific Methods

Compounds of Formula I or Formula II with benzofuran substitution at the6-position were prepared by methods analogous to those described inScheme 1.

The phenol 1 was iodinated using triiodoamine (generated in situ) toprovide the corresponding phenylacetic acid as indicated in Scheme 1.The acid was converted to the methyl ester under standard esterificationconditions. Treatment of the methyl ester with PdCl₂(PPh₃)₂ in thepresence of Cul led the formation of benzofuran 3. The benzofuran wasconverted to the mesylate 5. Mesylate 5 was either alklyated directlywith a secondary amine (such asN-(2,2-diphenylethyl)-N-(4-methoxy-benzyl)amine—prepared in Scheme 2) toform 6, or alkylated with a primary amine (such asN-2,2-diphenylethylamine) to form a secondary amine and then reductivelyaminated using a substituted benzaldehyde (such as2-chloro-3-trifluoromethylbenzaldehyde, 2,3-methylenedioxy)benzaldehyde,and 2,4-di-methoxy)benzaldehyde) to afford the tertiary amine 6. Themethyl ester 6 was then hydrolyzed using lithium hydroxide, and theresulting carboxylic acid was treated with 4 N HCl to form the tertiaryamine HCl salt I. The methyl ester 6 may also be converted to thecorresponding alcohol I by treatment of the ester with lithium aluminumhydride in THF.

The carboxylic acid/tertiary amine I was converted to the correspondingamide I by using a standard amidation procedure employing BOP,triethylamine, and an appropriate amine (ammonia or furfuryl-amine). Theamide I may be converted to the corresponding amine I by treatment ofthe amide with DIBAL-H in toluene.

Compounds of Formula I or Formula II with benzofuran substitution at the5-position were prepared by methods analogous to those described inScheme 2.

Treatment of the methyl ester with PdCl₂(PPh₃)₂ in the presence of Culled to the formation of benzofuran 8 as illustrated in Scheme 3. Thebenzofuran was next converted to the mesylate 9. Two synthetic routeswere utilized to prepare tertiary amine 11. In the first procedure, themesylate 9 was alkylated with a primary amine (such as(R)-(+)-□-methylphenylethylamine or (S)-(−)-□-methylphenylethylamine) toform the corresponding secondary amine. The secondary amine was thenreductively aminated with a substituted benzaldehyde (such as2-chloro-3-trifluoromethylbenzaldehyde and2,3-dihydrobenzo[b]furan-5-carboxaldehyde) to provide the tertiary amine11. In the second procedure, mesylate 9 was converted to the azide, andthen the azide was subjected to a catalytic hydrogenation to afford theprimary amine 10. The primary amine 10 was then reductively aminatedwith diphenylacetaldehyde to form the secondary amine, and the secondaryamine was subjected to a second reductive amination with a substitutedbenzaldehyde (such as 2-chloro-3-trifluoromethylbenzaldehyde,2,3-methylenedioxy)benzaldehyde, 2,4-di-methoxy)benzaldehyde,4-methoxybenzaldehyde and 2,3-dihydrobenzo[b]furan-5-carboxaldehyde) toafford 11. The methyl ester 11 was then hydrolyzed using lithiumhydroxide, and the resulting carboxylic acid was treated with 4 N HCl toform the tertiary amine HCl salt I.

Each of the above-described methods further include the optional step(s)of forming a pharmaceutically acceptable salt of a compound of thisinvention, and/or of forming a pharmaceutically acceptable solvate of acompound of this invention or a pharmaceutically acceptable saltthereof.

The following intermediates are useful in the methods described hereinto make the compounds of Formulas I and II:

-   -   2-[2-[(2,2-diphenylethyl)amino]ethyl]-5-benzofuran acetic acid        methyl ester,    -   2-[2-[[2-chloro-3-(trifluoromethyl)benzyl-(2,2-diphenylethyl)amino]ethyl]-5-benzofuran        acetic acid methyl ester,    -   2-[2-{[2,4-dimethoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran        acetic acid methyl ester,    -   2-[2-{[(2,3-methylenedioxy)benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran        acetic acid methyl ester,    -   2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran        acetic acid methyl ester,    -   2-[2-{[4-methoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran        acetic acid methyl ester,    -   (R)-2-[2-[(2-methyl-2-phenylethyl)amino]ethyl]-5-benzofuran        acetic acid methyl ester,    -   (R)-2-[2-{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuran        acetic acid methyl ester,    -   (R)-2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuran        acetic acid methyl ester,    -   (S)-2-[2-[(2-methyl-2-phenylethyl)amino]ethyl]-5-benzofuran        acetic acid methyl ester,    -   (S)-2-[2-[{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-benzofuran        acetic acid methyl ester,    -   (S)-2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuran        acetic acid methyl ester,    -   2-{2-[(2,2-diphenylethyl)amino]-ethyl}-6-benzofuran acetic acid        methyl ester,    -   2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuran        acetic acid methyl ester,    -   2-[2{[(2,3-methylenedioxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuran        acetic acid methyl ester,    -   2-[2{[(2,4-dimethoxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuran        acetic acid methyl ester,    -   2-{2-[(4-methoxy-benzyl)(2,2-diphenylethyl)amino]-ethyl}-6-benzofuran        acetic acid methyl ester    -   or a pharmaceutically acceptable salt or solvate thereof.

The following Test Methods and Examples are intended for illustrationonly and are not intended to limit the scope of the invention in anyway; the present invention being defined by the claims.

In the Test Methods and Examples, the following terms have thedesignated meaning: “pRSETa” is a known expression vector available fromInvitrogen; “IPTG” means isopropyl β-D-thiogalactopyranoside; “PO₄”means phosphate; “PBS” means phosphate buffered saline; “TBS” meanstris-buffered saline; EDTA means ethylenediamine tetraacetic acid; “DTT”means dithiothreitol; “FAF-BSA” means fatty-acid free bovine serumalbumin; “SRC-1” means steroid receptor coactivator 1; “CS” meanscharcoal stripped; “nM” means nanomolar; “μM” means micromolar; “mM”means millimolar; “pM” means picomolar; “mmol” means millimoles; “g”means grams; “ng” means nanograms; “mg/ml” means milligram permilliliter; “μL” means microliters; and “mL” means milliliter.

Test Method 1: Ligand Sensing Assay (LiSA) for LXRβ Agonist Activity

This assay measures the recruitment of a peptide derived from thecoactivator protein, SRC1, to the agonist-bound LXR□. Peptides derivedfrom other nuclear receptor cofactors may be similarly prepared andassayed.

To generate the human LXRP ligand binding domain suitable for LISA, amodified polyhistidine tag (MKKGHHHHHHG) (SEQ ID No. 1) was fused inframe to the human LXRβ ligand binding domain (amino acids 185-461 ofGenbank accession number U07132) and subcloned into the expressionvector pRSETa (Invitrogen) under the control of an IPTG inducible T7promoter. The human LXRβ ligand binding domain was expressed in E. colistrain BL21 (DE3). Ten-liter fermentation batches were grown in Rich PO₄media with 0.1 mg/mL Ampicillin at 25° C. for 12 hours, cooled to 920 C.and held at that temperature for 36 hours to a density of OD600=14. Atthis cell density, 0.25 mM IPTG was added and induction proceeded for 24hours at 9° C., to a final OD600=16. Cells were harvested bycentrifugation (20 minutes, 3500 g, 4° C.), and concentrated cellslurries were stored in PBS at −80° C.

Typically 25-50 g of cell paste is resuspended in 250-500 mL TBS, pH 8.0(25 mM Tris, 150 mM NaCl). Cells are lysed by passing 3 times through anAPV Rannie MINI-lab homogenizer and cell debris is removed bycentrifugation (30 minutes, 20,000 g, 4° C.). The cleared supernatant isfiltered through coarse pre-filters, and TBS, pH 8.0, containing 500 mMimidazole is added to obtain a final imidazole concentration of 50 mM.This lysate is loaded onto a column (XK-26, 10 cm) packed with Sepharose[Ni++ charged] Chelation resin (available from Pharmacia) andpre-equilibrated with TBS pH 8.0/50 mM imidazole. After washing tobaseline absorbance with equilibration buffer, the column is washed withapproximately one column volume of TBS pH-8.0 containing 95 mMimidazole. LXRβLBD(185-461) is eluted with a gradient from 50 to 500 mMimidazole. Column peak fractions are pooled immediately and diluted 5fold with 25 mM Tris pH 8.0, containing 5% 1,2-propanediol, 0.5 mM EDTAand 5 mM DTT. The diluted protein sample is then loaded onto a column(XK-16, 10 cm) packed with Poros HQ resin (anion exchange). Afterwashing to baseline absorbance with the dilution buffer the protein iseluted with a gradient from 50-500 mM NaCl. Peak fractions are pooledand concentrated using Centri-prep 10K (Amicon) filter devices andsubjected to size exclusion, using a column (XK-26, 90 cm) packed withSuperdex-75 resin (Pharmacia) pre-equilibrated with TBS, pH 8.0,containing 5% 1,2-propanediol, 0.5 mM EDTA and 5 mM DTT.

LXRβ protein was diluted to approximately 10 μM in PBS and five-foldmolar excess of NHS-LC-Biotin (Pierce) was added in a minimal volume ofPBS. This solution was incubated with gentle mixing for 30 minutes atambient room temperature. The biotinylation modification reaction wasstopped by the addition of 2000× molar excess of Tris-HCl, pH 8. Themodified LXRβ protein was dialyzed against 4 buffer changes, each of atleast 50 volumes, PBS containing 5 mM DTT, 2 mM EDTA and 2% sucrose. Thebiotinylated LXRβ protein was subjected to mass spectrometric analysisto reveal the extent of modification by the biotinylation reagent. Ingeneral, approximately 95% of the protein had at least a single site ofbiotinylation; and the overall extent of biotinylation followed a normaldistribution of multiple sites, ranging from one to nine.

The biotinylated protein was incubated for 20-25 minutes at aconcentration of 5 nM in assay buffer (50 mM NaF, 50 mM MOPS-pH 7.5, 0.1mg/ml FAF-BSA, 0.05 mM CHAPS, 10 mM DTT) with equimolar amounts ofstreptavidin-AlloPhycoCyanin (APC, Molecular Probes). At the same time,the biotinylated peptide comprising amino acids 676-700 of SRC-1(CPSSHSSLTERHKILHRLLQEGSPS-CONH2) (SEQ ID No. 2) at a concentration of10 nM was incubated in assay buffer with a ½ molar amount ofstreptavidin-labelled Europium (Wallac) for 20-25 minutes. After theinitial incubations are completed, a 20 molar excess of biotin was addedto each of the solutions to block the unattached streptavidin reagents.After 20 min at room temp, the solutions were mixed yielding aconcentration of 5 nM for the dye-labeled LXR protein and 10 nM forSRC-1 peptide.

49 uL of the protein/peptide mixture was added to each well of an assayplate containing 1 ul of test compound serial diluted in 100% DMSO. Thefinal volume in each well was 0.05 mL, and the concentration in the wellfor the dye-labeled protein and peptide was 5 nM protein and 10 nMSRC1-peptide. The final test compound concentrations were between 33 pMand 20 uM. The plates were incubated at room temp 2-hours and thencounted on a Wallac Victor V fluorescent plate reader.

In this assay 1 μM 24(S), 25-epoxycholesterol gave a reading of 20000fluorescence units over a background reading of 10000 fluorescenceunits.

Test Method 2: Ligand Sensing Assay for LXRα Agonist Activity

The assay for LXRα was run according to the procedures of Test Method 1,above using his-tagged LXRα ligand binding domain (amino acids 183-447of Genbank accession number U22662, with the 14^(th) amino acidcorrected to A from R). In this assay 1 μM 24(S),25-epoxycholesterolgave a reading of 20000 fluorescence units over a background reading of10000 fluorescence units.

EXAMPLE 12-[2-{[2-chloro-3-(trifluoromethyl)-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid hydrochloride

a) 4-Hydroxy-5-iodophenyl acetic acid methyl ester

The title compound was prepared according to the literature procedure(Kometani, T; Watt, D. S., and Ji, T. Tet.Lett. 26 (17), 2043-2046,1985).

b) 2-(2-hydroxy-ethyl)-5-benzofuran acetic acid methyl ester

To a stirring solution of 4-hydroxy-5-iodophenyl acetic acid methylester (1.04 g, 0.0035 mole) and 3-butyn-1-ol (0.5 g, 0.007 mole) in a3:1 solution of toluene/Et₃N (25 mL) was added PPh₃ (70 mg, 0.26 mmol),Cul (68 mg, 0.35 mmol), and Pd(PPh₃)₂Cl₂(50 mg, 0.07 mmol). The mixturewas heated at 118° C. for 1 h and then cooled to 50° C. To the reactionmixture was added florisil (2 g), the mixture was then stirred for 5min, cooled to RT, and filtered through a fretted funnel. The crudebenzofuran was concentrated and subjected to column chromatography oversilica gel (silica gel 60, EM Science) using 1% MeOH:CH₂Cl₂ as eluent toafford 0.65 g (78% yield) of the title compound as an oil. MS (ESI)235.0 (M+H⁺).

c) 2-[2-[(methanesulfonyl)oxy]ethyl]-5-benzofuran acetic acid methylester

To a cooled solution (0° C.) of 2-(2-hydroxy-ethyl)-5-benzofuran aceticacid methyl ester (1.5 g, 0.0064 mole) and triethylamine (0.78 g, 0.0077mole) in dichloromethane (50 mL) was added methanesulfonyl chloride (0.8g, 0.007 mole). The reaction mixture was warmed to RT and stirred for 1h. The reaction mixture was poured into H₂O, and extracted with CH₂Cl₂.The organic layer was washed with saturated aqueous NaCl, dried overNa₂SO₄, and filtered. The filterate was concentrated in vacuo to afford2.0 g (100% yield) of the title compound as an oil. MS (ESI) 313.0(M+H⁺).

d) 2-(2-azidoethyl)-5-benzofuran acetic acid methyl ester

To a stirring solution of 2-[2-[(methanesulfonyl)oxy]ethyl]-5-benzofuranacetic acid methyl ester (2.6 g, 8.33 mmol) in DMF (20 mL) was addedsodium azide (0.71 g, 0.011 mole). The reaction mixture was heated at75° C. for 2 h. Additional quantities of DMF (5 mL) and sodium azide(300 mg, 4.6 mmol) were added and the mixture was heated for 2 h. Thereaction mixture was cooled to RT, diluted with H₂O (40 mL), andextracted three times with EtOAc. The EtOAc extracts were washed withsaturated aqueous NaCl, dried over Na₂SO₄, and filtered. The filtratewas concentrated and the crude product was purified by columnchromatography over silica gel (silica gel 60,EM Science) using 10%EtOAc:hexane as eluent to afford 1.8 g (83%) of the title compound as anoil. IR: 2101.74 cm−¹, (N₃). ¹H-NMR (400 MHz, CDCl₃) δ□7.44-7.38 (m,2H), 7.18 (m, 1H), 6.51 (s, 1H), 3.72 (s, 3H), 3.62-3.71 (m, 4H), and3.07 (t, 2H, J=6.8 Hz).

e) 2-[2-[(2,2-diphenylethyl)amino]ethyl]-5-benzofuran acetic acid methylester

To a solution of 2-(2-azidoethyl)-5-benzofuran acetic acid methyl ester(1.5 g, 0.006 mole) in MeOH (50 mL) was added 10% palladium on carbon(0.35 g). The mixture was hydrogentated at atmospheric pressure for 0.5h. The catalyst was filtered using a fritted funnel and the filtrate wasconcentrated to a volume of 40 mL. The crude primary amine was usedwithout further purification. MS (ESI) 234.0 (M+H⁺).

To the stirring methanolic solution (above) of2-(2-aminoethyl)-5-benzofuran acetic acid methyl ester (ca. 6 mmol) wasadded diphenylacetaldehyde (1.06 g, 0.0054 mole) and a catalytic amountof p-toluenesulfonic acid monohydrate. The reaction mixture was stirredfor 45 min. and cooled to 0° C. To the stirring solution was addedsodium borohydride (0.3 g, 0.008 mole). The reaction mixture was stirredfor 2 h and then concentrated. The resulting residue was dissolved inEtOAc and washed with H₂O. The organic layer was washed with saturatedaqueous NaCl, dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude product was purified by column chromatography over silica gel(silica gel 60,EM Science) using 50% EtOAc:hexane to afford 0.5 g (22%)of the title compound as an oil. MS (ESI) 414.2 (M+H⁺).

f)2-[2-[[2-chloro-3-(trifluoromethyl)benzyl-(2,2-diphenylethyl)aminolethyl]-5-benzofuranacetic acid methyl ester

To a stirring solution of2-[2-[(2,2-diphenylethyl)amino]ethyl]-5-benzofuran acetic acid methylester (120 mg, 0.29 mmol) and 2-chloro-3-trifluoromethylbenzaldehyde(60.5 mg, 0.29 mmol) in dichloromethane (2 mL) was added sodiumtriacetoxyborohydride (68 mg, 0.32 mmol) and 1 drop of glacial aceticacid. The reaction was stirred for 4 h at RT, and then was diluted withEtOAc. The reaction mixture was washed with saturated aqueous NH₄Cl,saturated aqueous NaHCO₃, and saturated aqueous NaCl. The organic layerwas dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by column chromatography over silica gel (Silicagel 60,EM Science) using 10% EtOAc:hexane as eluent to afford the titlecompound as an oil (0.17 g, 100%). MS (ESI) 606.2 (M+H⁺).

g)2-[2-[[2-chloro-3-(trifluoromethyl)benzyl-(2,2-diphenylethyl)amino]ethyl]-5-benzofuranacetic acid hydrochloride

To a stirring solution of2-[2-[[2-chloro-3-(trifluoromethyl)benzyl-(2,2-diphenylethyl)amino]ethyl]-5-benzofuranacetic acid methyl ester (170 mg, 0.28 mmol) in tetrahydrofuran (2.5 mL)and H₂O (0.7 mL) was added LIOH H₂O (26 mg, 0.616 mmol). The reactionmixture was stirred overnight and then concentrated in vacuo. Theresulting residue was diluted with H₂O (3 mL) and the aqueous mixturewas acidified to pH=1.5 with 1 N HCl (aqueous). The aqueous solution wasthen extracted three times with EtOAc. The organic layer was washed withH₂O and saturated aqueous NaCl. The organic extracts were then driedover Na₂SO₄, filtered, and concentrated to provide the tertiary amine asan oil. The amine was dissolved in Et₂O and acidified with 1.0 NHCl/Et₂O. The acidic solution was concentrated in vacuo to afford 74.8mg (43%) of the title compound as a white solid. MS (ESI) 591.8 (M+H⁺).

EXAMPLE 22-[2-{[2,4-dimethoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid hydrochloride

Following the procedure of Example 1(a)-(g) except2,4-dimethoxybenzaldehyde was used in step 1(f) instead of2-chloro-3-trifluoromethylbenzaldehyde, the title compound was obtainedas a white powder (4% overall). MS (ESI) 550.0 (M+H⁺).

EXAMPLE 32-[2-{[(2,3-Methylenedioxy)benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid hydrochloride

Following the procedure of Example 1(a)-(g) except2,3-(methylenedioxy)benzaldehyde was used in step 1(f) instead of2-chloro-3-trifluoromethylbenzaldehyde, the title compound was obtainedas a white powder (9% overall). MS (ESI) 534.0 (M+H⁺).

EXAMPLE 42-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid hydrochloride

Following the procedure of Example 1(a)-(g) except2,3-dihydrobenzo[b]furan-5-carboxaldehyde was used in step 1(f) insteadof 2-chloro-3-trifluoromethylbenzaldehyde, the title compound wasobtained as a white powder (5% overall). MS (ESI) 532.0 (M+H⁺).

EXAMPLE 52-[2-{[4-Methoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid hydrochloride

Following the procedure of Example 1(a)-(g) except 4-methoxybenzaldehydewas used in step 1(f) instead of 2-chloro-3-trifluoromethylbenzaldehyde,the title compound was obtained as a white powder (11% overall). MS(ESI) 520.2 (M+H⁺).

EXAMPLE 6(R)-2-[2-{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid hydrochloride

a) (R)-2-[2-[(2-methyl-2-phenylethyl)amino]ethyl]-5-benzofuran aceticacid methyl ester

To a stirring solution of 2-[2-[(methanesulfonyl)oxy]ethyl]-5-benzofuranacetic acid methyl ester (100 mg, 0.32 mmol) in CH₃CN (10 mL) was added(R)-(+)-β-methylphenylethylamine (44 mg, 0.32 mmol) and K₂CO₃ (140 mg,1.0 mmol). The reaction mixture was heated at reflux overnight. Thereaction mixture was concentrated in vacuo and the residue was dilutedwith H₂O (10 mL). The aqueous mixture was extracted three times withEtOAc. The organic layer was washed with saturated aqueous NaCl, driedover Na₂SO₄, and filtered. The filtrate was concentrated and the crudeproduct was purified by column chromatography over silica gel (silicagel 60,EM Science) using 55% EtOAc-hexane to afford 46.8 mg (43%) of thetitle compound as a white solid. MS (ESI) 352.0 (M+H⁺).

b)(R)-2-[2-{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid methyl ester

To a stirring solution of(R)-2-[2-[(2-methyl-2-phenylethyl)amino]ethyl]-5-benzofuran acetic acidmethyl ester (73 mg, 0.21 mmol) and2-chloro-3-trifluoromethylbenzaldehyde (44 mg, 0.21 mmol) indichloromethane (4 mL) was added sodium triacetoxyborohydride (47 mg,0.22 mmol) and 1 drop of glacial acetic acid. The reaction mixture wasstirred overnight at RT, and was diluted with EtOAc. The reactionmixture was then washed with saturated aqueous NH₄Cl, saturated aqueousNaHCO₃, and saturated aqueous NaCl. The organic layer was dried overNa₂SO₄, and filtered. The filtrate was concentrated and the crudeproduct was purified by column chromatography over silica gel (Silicagel 60, EM Science) using 10% EtOAc:hexane as eluent to afford 73 mg(65%) of the title compound as an oil. MS (ESI) 543.8 (M+H⁺).

c)(R)-2-[2-{2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid hydrochloride

To a stirring solution of(R)-2-[2-{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid methyl ester (73 mg, 0.13 mmol) in THF (2.5 mL) and H₂O (0.7mL) was added LiOH.H₂O (12 mg, 0.32 mmol). The reaction mixture wasstirred overnight and then concentrated in vacuo. The resulting residuewas diluted with H₂O (3 mL) and the aqueous mixture was acidified topH=1.5 with 1 N HCl (aqueous). The aqueous solution was then extractedthree times with EtOAc. The organic layer was washed with H₂O andsaturated aqueous NaCl. The extracts were then dried over Na₂SO₄,filtered, and concentrated to provide the tertiary amine as an oil. Theoil was dissolved in Et₂O and acidified with 1.0 N HCl/Et₂O. The acidicsolution was concentrated in vacuo to afford the title compound as awhite solid (27.7 mg, 38%). MS (ESI) 530.8 (M+H⁺).

EXAMPLE 7(R)-2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid hydrochloride

Following the procedure of Example 6(a)-(c) except2,3-dihydrobenzo[b]furan-5-carboxaldehyde was used in step 6(b) insteadof 2-chloro-trifluromethylbenzaldehyde, the title compound was obtainedas a white powder (15% overall). MS (ESI) 470.0 (M+H⁺).

EXAMPLE 8(S)-2-[2-[{[2-Chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-benzofuranacetic acid hydrochloride

Following the procedure of Example 6(a)-(c) except(S)-(−)-β-methylphenylethylamine was used in step 6(a) instead of(R)-(+)-β-methylphenylethylamine, the title compound was obtained as awhite powder (10% overall). MS (ESI) 530.0 (M+H⁺).

EXAMPLE 9(S)-2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid hydrochloride

Following the procedure of Example 6(a)-(c) except(S)-(−)-β-methylphenylethylamine was used in step 6(a) instead of(R)-(+)-β-methylphenylethylamine, and in addition,(2,3-dihydrobenzo[b]furan-5-carboxaldehyde was used in step 6(b) insteadof 2-chloro-trifluoromethylbenzaldehyde, the title compound was obtainedas a white powder (9% overall). MS (ESI) 470.0 (M+H⁺).

EXAMPLE 102-{2-[[2-Chloro-3(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid hydrochloride

a) (3-hydroxy-4-iodo-phenyl)-acetic acid methyl ester

To a stirring solution of (3-hydroxy-phenyl)-acetic acid (5.0 g, 0.033mole) in aqueous NH₂OH (100 mL NH₂OH (aqueous) and 50 mL H₂O at 0° C.was added solid Kl (7.6 g, 0.36 mole) and solid I₂ (6.0 g, 0.030 mole).The reaction mixture was stirred for 2 h, and then poured into H₂O. Theaqueous mixture was extracted three times with Et₂O, and the organicextracts were combined. The ether extracts were dried over Na₂SO₄,filtered, and concentrated. The crude product was dissolved in MeOH (100mL), conc. HCl (2 mL) was added, and the mixture was heated at refluxovernight. The reaction was cooled to RT and concentrated. The crudemethyl ester was dissolved in EtOAc, and washed two times with H₂O (50mL). The EtOAc layer was dried over Na₂SO₄, filtered, and concentrated.The crude product was purified by preparative HPLC (TMC CombiPrep PDS,75×30 mm, 25 mL/min, acetonitrile: H₂O, UV detection at 254 nm) to give2.67 g (29% yield) of title compound as a white solid. MS(ESI) 292.8(M⁺).

b) 2-(2-hydroxy-ethyl)-6-benzofuran acetic acid methyl ester

To a stirring solution of (3-hydroxy-4-iodo-phenyl)-acetic acid methylester (1.04 g, 0.0035 mole) and 3-butyn-1-ol (0.5 g, 0.007 mole) in a3:1 solution of toluene/Et₃N (25 mL) was added PPh₃ (70 mg, 0.26 mmol),Cul (68 mg, 0.35 mmol), and Pd(PPh₃)₂Cl₂(50 mg, 0.07 mmol). The mixturewas heated at 118° C. for 1 h and then cooled to RT. To the reactionmixture was added florisil (2 g) and the mixture was filtered through afritted funnel. The crude benzofuran was concentrated and subjected tocolumn chromatography over silica gel (silica gel 60, EM Science) using40% EtOAc:hexane as eluent to afford 0.59 g (71% yield) of the titlecompound as an oil. MS (ESI) 235.0 (M+H⁺).

c) 2-{2-[(2,2-diphenylethyl)amino]-ethyl}-6-benzofuran acetic acidmethyl ester

To a stirring solution 2-[2-(2-hydroxy-ethyl)-benzofuran]acetic acidmethyl ester (0.33 g, 0.0014 mole) in CH₂Cl₂ (15 mL) at 0° C. was addedEt₃N (0.21 mL, 0.0015 mole) and methanesulfonyl chloride (0.12 mL,0.0015 mole). The reaction mixture was stirred for 3 h at 0° C. Themixture was then poured into cold H₂O, and extracted two times withCH₂Cl₂ (30 mL). The CH₂Cl₂ extracts were washed with saturated aqueousNaCl, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudemesylate (prepared above) was dissolved in CH₃CN (25 mL), and thefollowing reagents were added to the solution: solid K₂CO₃ (194 mg, 1.41mmol) and N-2,2-diphenylethylamine (0.55 g, 0.0014 mole). The reactionmixture was heated overnight at 88° C. The mixture was filtered througha fritted funnel and concentrated. The crude product was purified bypreparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H₂O, UV detection at 254 nm) to give 125 mg (15% yield) of the titlecompound as a viscous oil. MS(ESI) 400.0 (M+H⁺).

d)2-{2-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid methyl ester

To a stirring solution of2-{2-[(2,2-diphenylethyl)amino]-ethyl}-6-benzofuran acetic acid methylester (160 mg, 0.39 mmol) and 2-chloro-3-trilfuoromethylbenzaldehyde (81mg, 0.39 mmol) in CH₂Cl₂ (4 mL) was added sodium triacetoxyborohydride(91 mg, 0.43 mmol) and two drops of glacial acetic acid. The mixture wasstirred for 4 h, and was diluted with EtOAc (10 mL). The mixture waswashed with saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, andsaturated aqueous NaCl. The organic layer was dried over Na₂SO₄,filtered, and concentrated. The crude product was purified by columnchromatography over silica (Silica gel 60, EM Science) using 10% EtOAc:Hexane as eluent to afford 0.15 g (64%) of the title compound as an oil.MS(ESI) 606.2 (M⁺).

e)2-[2-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid hydrochloride

To a stirring solution of2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid methyl ester (150 mg, 0.25 mmol) in a 4:1 H₂O/THF (3 mL)solution at 0° C. was added LiOH—H₂O (23 mg, 0.55 mmol). The reactionmixture was warmed to RT and stirred overnight. The reaction mixture wasconcentrated to remove the THF and was diluted with H₂O (5 mL). Theaqueous solution was acidified with 1 N HCl (10 mL) and extracted threetimes with EtOAc. The EtOAc extracts were dried over Na₂SO₄, filtered,and concentrated. The resulting tertiary amine was dissolved in Et₂O andacidified with 1 N HCl in Et₂O. The solution was stirred for 20 min. andthen concentrated to afford 122 mg (78% yield) of the title compound asa white solid. MS(ESI) 592.0.(M⁺).

EXAMPLE 112-[2-{[(2,3-Methylenedioxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuranacetic acid hydrochloride

Following the procedure of Example 10(a)-(e) except(2,3-methylenedioxy)benzaldehyde was used in step 10(d) instead of2-chloro-3-trifluoromethylbenzaldehyde, the title compound was preparedas a white solid (3% overall). MS (ESI) 534.2 (M+H⁺).

EXAMPLE 122-[2-{[(2,4-dimethoxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuranacetic acid hydrochloride

Following the procedure of Example 10(a)-(e) except(2,4-di-methoxy)benzaldehyde was used in step 10(d) instead of2-chloro-3-trifluoromethylbenzaldehyde, the title compound was preparedas a white solid (4% overall). MS (ESI) 550.2 (M+H⁺).

EXAMPLE 132-{2-[(4-Methoxy-benzyl)(2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid hydrochloride

a) N-(2,2-Diphenylethyl)-N-(4-methoxy-benzyl)amine

To a stirring solution of 4-methoxybenzylamine (1.4 g, 0.010 mole) and2,2-diphenylacetaldehyde (2.0 g, 0.010 mole) in dichloromethane (50 mL)was added sodium triacetoxyborohydride (2.38 g, 0.011 mole) and aceticacid (2.0 mL). The reaction mixture was stirred overnight. The reactionmixture was concentrated and the residue was dissolved in EtOAc. TheEtOAc solution was washed with saturated aqueous NaHCO₃. The organicextracts were dried over Na₂SO₄, filtered, and concentrated. The crudemixture was subjected to column chromatography over silica gel (silicagel 60, EM Science) using 30% EtOAc: Hexane as eluent to afford 1.75 g(54% yield) of the title compound as a yellow oil. MS (ESI) 318.0(M+H⁺).

b) 2-{2-[(4-Methoxy-benzyl)(2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid methyl ester

Following the procedure of Example 10-step 10(c), exceptN-(2,2-diphenylethyl)-N-(4-methoxy-benzyl)amine was used instead ofN-2,2-diphenylethylamine the title compound was prepared as a whitesolid (45 mg, 27% overall). MS(ESI) 534.0 (M+H⁺).

c) 2-{2-[(4-Methoxy-benzyl)(2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid hydrochloride

Following the procedure of Example 10-step 10(e), except2-{2-[(4-methoxy-benzyl)(2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid methyl ester was used in step 10(e) instead of2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid methyl ester, the title compound was prepared as a whitesolid (42 mg, 86%). MS (ESI) 520.2 (M+H⁺).

EXAMPLE 142-{2-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl-amino]ethyl}-benzofuran-6-yl)-N-furan-2-ylmethyl-acetamide hydrochloride

To a stirring mixture of2-{2-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-ethyl}-benzofuran-6-yl)-acetic acid (0.19 g, 0.32 mmol), furfurylamine (0.031 g, 0.32 mmol) andacetonitrile (5 mL) was added BOP reagent (0.146 g, 0.33 mmol). Afterstirring overnight at RT, the reaction mixture was diluted with EtOAcand washed with saturated NaHCO₃, water, 0.01 N HCl (aq.) and brine. Theorganic extract was dried over MgSO₄ and filtered. After concentrationof the filtrate in vacuo, the crude product was purified by columnchromatography over silica gel (silica gel 60, EM Science ) using 30%EtOAc:hexane as eluent to afford 0.166 g (78%) of the title compound asan oil. MS(ESI) 671.2 (M+H⁺)

EXAMPLE 152-{2-[(2,4-Dimethoxy-benzyl)(2,2-diphenylethyl)-amino]ethyl}-benzofuran-6-yl)-N-furan-2-ylmethyl-acetamide hydrochloride

Following the procedure of Example 14 (above) except2-{2-[(2,4-dimethoxy-benzyl)(2,2-diphenylethyl-amino]ethyl}-benzofuran-6-yl)-acetic acid (Example 12) was used instead of2-{2-[(2-chloro-3-(trifluoromethyl)-benzyl)(2,2-diphenylethyl-amino]ethyl}-benzofuran-6-yl)-acetic acid the titlecompound was obtained as a foam (25%). MS(ESI): 629.4 (M+H⁺).

EXAMPLE 16 2-{2-[(2(Chloro-3-(trifluoromethyl)-benzyl)(2,2-diphenylethyl-amino]ethyl}-benzofuran-6-yl)-acetamidehydrochloride

Following the procedure of Example 14 except NH₃ in dioxane (0.5 M) wasused instead of furfurylamine, the title compound was obtained as a foam(44%). MS(ESI): 591.2 (M+H⁺)

EXAMPLE 17 (Racemic) 2-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2-phenyl-propyl)-amino]-propyl}-benzofuran-6-yl)-aceticacid hydrochloride

a) [2-(2-azido-ethyl)-benzofuran-6-yl]-acetic acid methyl ester

To a stirring solution 2-[2-(2-hydroxy-ethyl)-benzofuran]acetic acidmethyl ester (0.33 g, 0.0014 mol-Example 10 steps (a)-(b)) in CH₂Cl₂ (15mL) at 0° C. was added Et₃N (0.21 mL, 0.0015 mole) and methanesulfonylchloride (0.12 mL, 0.0015 mole). The reaction mixture was stirred for 3h at 0° C. The mixture was then poured into cold H₂O, and extracted twotimes with CH₂Cl₂ (30 mL). The CH₂Cl₂ extracts were washed withsaturated aqueous NaCl, dried over Na₂SO₄, filtered, and concentrated invacuo to afford the corresponding mesylate.

To a stirring solution of the mesylate (0.53 g, 1.71 mmol) inacetonitrile (15 ml) was added sodium azide (0.16 g, 2.56 mmol). Thereaction was heated to 85° C. for 1.5 h and then cooled to roomtemperature. The reaction mixture was poured into H₂O (50 ml) andextracted twice with ethyl acetate. The organic extracts were dried overNa₂SO₄, filtered, and concentrated. The crude product was subjected tocolumn chromatography over silica gel (silica gel 60, EM Science) using15% EtOAc:hexane as eluent to afford the title compound as a clear oil,380 mg (85%). MS (ESI) 260.0 (M−H⁺).

b) 2-{2-[2-Phenyl-propylamino]-ethyl}-6-benzofuran acetic acid methylester

To a stirring solution of [2-(2-azido-ethyl)-benzofuran-6-yl]-aceticacid methyl ester (380 mg, 1.45 mmol) in MeOH (7 ml) was added 10%palladium on carbon (30 mg) and the reaction mixture was hydrogenated atatomospheric pressure for 1 h. The mixture was filtered, concentrated,and the crude amine was used in the subsequent step without furtherpurification. MS (ESI) 234.0 (M+H⁺)

To a stirring solution of the crude amine (above) in CH₂Cl₂ (10 ml) wasadded 2-phenyl-propionaldehyde (0.20 ml, 1.52 mmol). To this mixture wasadded TFA (1 ml) and sodium triacetoxyborohydride (0.4 g, 1.9 mmol) andthe reaction mixture was stirred overnight. The reaction mixture waspoured into H₂O (20 ml) and extracted twice with ethyl acetate. Theorganic extracts were dried over Na₂SO₄, filtered, and concentrated. Thecrude product was subjected to column chromatography over silica gel(silica gel 60, EM Science) using 30% EtOAc:hexane as eluent to affordthe title compound as a yellow oil, 0.15 g (30%). MS (ESI) 352.4 (M+H⁺).

c)2-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2-phenyl-propyl)-amino]-propyl}-benzofuran-6-yl)-aceticacid hydrochloride

Following the procedure of Example 10(d)-(e) except2-{2-[2-phenyl-propylamino]-ethyl}-6-benzofuran acetic acid methyl esterwas employed in step (d) instead of2-{2-[(2,2-diphenylethyl)amino]-ethyl}-6-benzofuran acetic acid methylester the title compound was prepared as a white solid, 38 mg (51%). MS(ESI) 529.8 (M+H⁺).

EXAMPLE 182-(2-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl-(2,2-diphenylethyl)-amino]-propyl)benzofuran-6-yl)-ethanolhydrochloride

To a stirring mixture of2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino-ethyl}-6-benzofuranacetic acid methyl ester (0.1 g, 0.165 mmol-Example 10(a)-(c)) and ether(15 mL) at −15° C. was added LAH (1 M in THF, 0.5 mL, 0.5 mmol)dropwise. After stirring for 1 h, the reaction mixture was quenched withsaturated aqueous NH₄Cl and stirred for 15 min. MgSO₄ was added and theheterogenous mixture was filtered. The filtrate was concentrated invacuo and the resulting oil was converted to the HCl salt using 1.0 MHCl/ether to provide the title compound as a white solid, 65 mg (65%) MS(ESI) 578.4 (M+H⁺).

EXAMPLE 192-(2-{3-[(2,4Dimethoxy)-benzyl-(2,2-diphenylethyl)-amino]-propyl}-benzofuran-6-yl)-ethanolhydrochloride

Following the procedure of Example 18 except2-{2-[[2,4-dimethoxy)benzyl](2,2-diphenylethyl)amino-ethyl}-6-benzofuran acetic acid methyl ester(Example 12) was used instead of2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino-ethyl}-6-benzofuranacetic acid methyl ester the title compound was prepared as a whitesolid (66%). MS (ESI) 536.2 (M+H⁺).

EXAMPLE 202-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-((R)-2-phenyl-propyl)-amino]-propyl}-benzofuran-6-yl)-aceticacid hydrochloride

Following the procedure of Example 10(a-e) except(R)-(+)-β-methylphenylethylamine was used instead ofN-2,2-diphenylethylamine in step 10(c) the title compound was preparedas a white solid (2% overall). MS (ESI) 530.2 (M+H⁺).

EXAMPLE 212-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-((S)-2-phenyl-propyl)-amino]-propyl)benzofuran-6-yl)-aceticacid hydrochloride

Following the procedure of Example 10(a-e) except(S)-(−)-β-methylphenylethylamine was used instead ofN-2,2-diphenylethylamine in step 10(c) the title compound was preparedas a white solid (1.5% overall). MS (ESI) 530.2 (M+H⁺).

EXAMPLE 22(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-{2-[(furan-2-ylmethyl)-amino]-ethyl-benzofuran-2-yl)-propyl]-aminedihydrochloride

To a stirring solution of2-{2-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl-amino]ethyl}-benzofuran-6-yl)-N-furan-2-ylmethyl-acetamide (0.16 g, 0.24 mmol-Example 14) in THF (1.5 mL) wasadded DIBAL-H (1.5 M in toluene, 0.32 mL, 0.48 mmol). After stirringunder argon overnight, the reaction mixture was quenched with saturatedNH₄Cl and extracted with EtOAc. The organic layer was washed with water,brine and dried over MgSO₄. The organic extracts were filtered and thenconcentrated in vacuo. The crude product was purified by columnchromatography over silica gel (silica gel 60, EM Science) using 0.5%MeOH: 0.1% conc. NH₄OH: dichloromethane to afford the title compound asan oil. The free base was converted to the HCl salt using 0.1 MHCl/ether to provide the title compound as a white solid, 31%. MS (ESI)657.2 (M+H⁺).

The above description fully discloses how to make and use the presentinvention. However, this invention is not limited to the particularembodiments described hereinabove, but includes all modification thereofwithin the scope of the appended claims and their equivalents. Thoseskilled in the art will recognize through routine experimentation thatvarious changes and modifications can be made without departing from thescope of this invention. The various references to journals, patents andother patent applications that are cited herein are incorporated byreference herein as though fully set forth.

1. A compound of Formula I:

wherein: X is CH or N; Y is N(R¹⁰), O, or S, wherein t is 0 or 1 when Yis N(R¹⁰) or O, and t is 0 when Y is S; U is selected from halo, —OR¹⁰,—NR¹⁴R¹⁵, nitro, cyano, —COOR¹⁰, —COR¹³, —OCOR¹³, —CONR¹⁴R¹⁵,—N(R¹⁴)COR¹³, —SO₃H, —SO₂NR¹⁴R¹⁵, —C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁴)SO₂R¹⁶, and a5 or 6-membered heterocyclic group; A is a phenyl fused ring moiety or apyridyl fused ring moiety, wherein when A is a phenyl ring moiety, k is0-3 and t is 0 or 1 and when A is a pyridyl ring moiety, k is 0-2 and tis 0; W¹ is selected from C₃-C₈ cycloalkyl, aryl and Het, wherein saidC₃-C₈ cycloalkyl, Ar and Het are optionally unsubstituted or substitutedwith one or more groups independently selected from halo, cyano, nitro,C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³ , —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents; W² is selected from H,halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹²,—C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹²,—C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents, andwherein the C₃-C₇ cycloalkyl, Ar and Het moieties of said —C₀-C₆alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl areoptionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰,—C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents; W³ is selected from thegroup consisting of: H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹²,—C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar and —C₁-C₆alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents; Q isselected from C₃-C₈ cycloalkyl, Ar and Het; wherein said C₃-C₈cycloalkyl, Ar and Het are optionally unsubstituted or substituted withone or more groups independently selected from halo, cyano, nitro, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; p is 0-8; n is 2; m is 0or 1; q is 0 or 1; t is 0 or 1; each R¹ and R² are independentlyselected from H, halo, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-Het,—C₁-C₆ alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹ and R² togetherwith the carbon to which they are attached form a 3-5 memberedcarbocyclic or heterocyclic ring, wherein said heterocyclic ringcontains one, or more heteroatoms selected from N, O, and S, where saidC₁-C₆ alkyl is optionally unsubstituted or substituted by one or morehalo substituents; each R³ is the same or different and is independentlyselected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇cycloalkyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, wherein said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; each R⁴ and R⁵ isindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R⁶ and R⁷ are eachindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R⁸ and R⁹ are eachindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹⁰ is selected fromH, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; each R¹¹ and each R¹² areindependently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇cycloalkyl, or R¹¹ and R¹² together with the nitrogen to which they areattached form a 4-7 membered heterocyclic ring which optionally containsone or more additional heteroatoms selected from N, O, and S; R¹³ isselected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹⁴ andR¹⁵ are each independently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl,C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇cycloalkyl, —C₀-C₆ alkyl-O—Ar, —C₀-C₆ alkyl-O-Het, —C₀-C₆ alkyl-O—C₃-C₇cycloalkyl, —C₀-C₆ alkyl-S(O)_(x)-C₁-C₆ alkyl, —C₀-C₆ alkyl-S(O)_(x)—Ar,—C₀-C₆ alkyl-S(O)_(x)-Het, —C₀-C₆ alkyl-S(O)_(x)-C₃-C₇ cycloalkyl,—C₀-C₆ alkyl-NH—Ar, —C₀-C₆ alkyl-NH-Het, —C₀-C₆ alkyl-NH-C₃-C₇cycloalkyl, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₆ alkyl-N(C₁-C₄alkyl)-Het, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, where x is0, 1 or 2, or R¹⁴ and R¹⁵, together with the nitrogen to which they areattached, form a 4-7 membered heterocyclic ring which optionallycontains one or more additional heteroatoms selected from N, O, and S,wherein said C₁-C₆ alkyl is optionally substituted by one or more of thesubstituents independently selected from the group halo, —OH, —SH, —NH₂,—NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, —CO₂H,—CO₂(unsubstituted C₁-C₆ alkyl), —CONH₂, —CONH(unsubstituted C₁-C₆alkyl), —CON(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl),—SO₃H, —SO₂NH₂, —SO₂NH(unsubstituted C₁-C₆ alkyl) and—SO₂N(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl); R¹⁶ isC₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; and R¹⁷ is H, C₁-C₆alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; or a pharmaceuticallyacceptable salt or solvate thereof.
 2. The compound according to claim1, wherein p is 0, 1 or
 2. 3. The compound according to claim 1, whereint is
 0. 4. The compound according to wherein R¹ and R² are each H. 5.The compound according to claim 1, wherein A is a phenyl fused ring. 6.The compound according to claim 1, wherein k is
 0. 7. The compoundaccording to claim 1, wherein U is U is —OR¹⁰, —COOR¹⁰, —CONR¹¹R¹² or—NR¹¹R¹².
 8. The compound according to claim 1, wherein U is —OH, —COOH,—CONH₂, —CON(H)CH₂-furan-2-yl, or —N(H)CH₂-furan-2-yl. 9-10. (canceled)11. The compound according to claim 1, wherein q is
 1. 12. The compoundaccording to claim 1, wherein R⁸ and R⁹ are each H.
 13. The compoundaccording to claim 1, wherein Q is a substituted phenyl group,containing one or two substituents selected from halo, C₁-C₄ alkoxy; andC₁-C₄ alkyl or Q is a 1,3-benzodioxolyl or dihydrobenzofuranyl group.14. The compound according to claim 1, wherein Q is a phenyl groupsubstituted by one or two substituents selected from chloro,trifluoromethyl and methoxy or is a 1,3-benzodioxolyl or adihydrobenzofuranyl group.
 15. The compound according to claim 1,wherein m is 1 and R⁶ and R⁷ are both H.
 16. The compound according toclaim 1, wherein W³ is H
 17. The compound according to claim 1 whereinW¹ and W² are each unsubstituted phenyl or W¹ is unsubstituted phenyland W² is methyl.
 18. A compound of Formula II:

wherein: X is CH or N; Y is O, or S; U is selected from halo, —OR¹⁰,—NR¹⁴R¹⁵, cyano, —COOR¹⁰, —OCOR¹³, —CONR¹⁴R¹⁵, —N(R¹⁴)COR¹³,—SO₂NR¹⁴R¹⁵, —C(═NH)NR¹⁴R¹⁵, and a 5 or 6-membered heterocyclic group; Ais a phenyl fused ring moiety, wherein k is 0 or 1; W¹ is selected fromC₃-C₈ cycloalkyl, aryl and Het, wherein said C₃-C₈ cycloalkyl, Ar andHet are optionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰,—C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄ alkyl-NR¹¹R¹² —C₀-C₄alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SO₃H,—C₀-C₄alkyl-SO₂NR¹¹R¹², —C₀-C₄ alkyl-SO₂R¹⁰, —C₀-C₄ alkyl-SOR¹³, —C₀-C₄alkyl-OCOR¹³, —C₀-C₄ alkyl-OC(O)NR¹¹R¹², —C₀-C₄ alkyl-OC(O)OR¹³, —C₀-C₄alkyl-NR¹¹C(O)OR¹³, —C₀-C₄ alkyl-NR¹¹ C(O)NR¹¹R¹², and —C₀-C₄alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; W² is selected from H,halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₀-C₄ alkyl-NR¹¹R¹²,—C₀-C₄ alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄alkyl-C(O)SR¹⁰, —C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄alkyl-OCOR¹³, —C₀-C₄ alkyl-OCONR¹¹R¹², —C₀-C₄ alkyl-NR¹¹CONR¹¹R¹²,—C₀-C₄ alkyl-NR¹¹COR¹³, —C₀-C₄ alkyl-Het, —C₀-C₄ alkyl-Ar and —C₀-C₄alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents, andwherein the C₃-C₇ cycloalkyl, Ar and Het moieties of said —C₀-C₄alkyl-Het, —C₀-C₄ alkyl-Ar and —C₀-C₄ alkyl-C₃-C₇ cycloalkyl areoptionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰,—C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SO₃H, —C₀-C₄alkyl-SO₂N¹¹R¹², —C₀-C₄ alkyl-SO₂R¹⁰, —C₀-C₄ alkyl-SOR ³, —C₀-C₄alkyl-OCOR¹³, —C₀-C₄ alkyl-OC(O)NR¹¹R¹², —C₀-C₄ alkyl-OC(O)OR¹³, —C₀-C₄alkyl-NR¹¹C(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; W³ is selected from thegroup consisting of: H, halo, C₁-C₆ alkyl, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-CO₂R¹⁰,—C₀-C₄alkyl-C(O)SR¹⁰, —C₀-C₄alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄alkyl-OCOR¹³, —C₀-C₄ alkyl-OCONR¹¹R¹², —C₀-C₄ alkyl-NR¹¹CONR¹¹R¹²,—C₀-C₄ alkyl-NR¹¹COR¹³, —C₀-C₄ alkyl-Het, —C₁-C₄ alkyl-Ar and —C₁-C₄alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents; Q is Aror Het; wherein said Ar and Het are optionally unsubstituted orsubstituted with one or more groups independently selected from halo,cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₄alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR^(10l , —C) ₀-C₄ alkyl-CONR¹¹R¹²,—C₀-C₄ alkyl-COR¹³, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄alkyl-OR¹⁰, —C₀-C₄ alkyl-SO₃H, —C₀-C₄ alkyl-SO₂NR¹¹R¹², —C₀-C₄alkyl-SO₂R¹⁰, —C₀-C₄ alkyl-SOR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄alkyl-OC(O)NR¹¹R¹², —C₀-C₄ alkyl-OC(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)OR¹³,—C₀-C₄ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄ alkyl-NR¹¹COR¹³, where saidC₁-C₆ alkyl is optionally unsubstituted or substituted by one or morehalo substituents, p is 0-4; n is 2; m is 0 or 1; q is 0 or 1; t is 0;each R¹ and R² are independently selected from H, fluoro, C₁-C₆ alkyl,—C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SR¹⁰, —C₁-C₄ alkyl-Het, —C₁-C₄ alkyl-Arand —C₁-C₄ alkyl-C₃-C₇ cycloalkyl, where said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents; each R³is the same or different and is independently selected from halo, cyano,C₁-C₆ alkyl, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄alkyl-SO₂NR¹¹R¹², and —C₀-C₄ alkyl-CO₂H, wherein said C₁-C₆ alkyl isoptionally unsubstituted or substituted by one or more halosubstituents; each R⁴ and R⁵ is independently selected from H, fluoroand C₁-C₆ alkyl; R⁶ and R⁷ are each independently selected from H.fluoro and C₁-C₆ alkyl; R⁸ and R⁹ are each independently selected fromH, fluoro and C₁-C₆ alkyl; R¹⁰ is selected from H, C₁-C₆ alkyl, —C₀-C₄alkyl-Ar, —C₀-C₄ alkyl-Het and —C₀-C₄ alkyl-C₃-C₇ cycloalkyl; each R¹¹and each R¹² are independently selected from H, C₁-C₆ alkyl, —C₀-C₄alkyl-Ar, —C₀-C₄ alkyl-Het and —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, or R¹¹ andR¹² together with the nitrogen to which they are attached form a 4-7membered heterocyclic ring which optionally contains one or moreadditional heteroatoms selected from N, O, and S; R¹³ is selected fromC₁-C₆ alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het and —C₀-C₄ alkyl-C₃-C₇cycloalkyl; R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-Ar, -CO-C₄ alkyl-Het,—C₀-C₄ alkyl-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-O—Ar, —C₀-C₄ alkyl-O-Het,—C₀-C₄ alkyl-O—C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-S(O)_(x)-C₁-C₆ alkyl,—C₀-C₄ alkyl-S(O)_(x)—Ar, —C₀-C₄ alkyl-S(O)_(x)-Het, —C₀-C₄alkyl-S(O)_(x)-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-NH—Ar, —C₀-C₄alkyl-NH-Het, —C₀-C₄ alkyl-NH—C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-N(C₁-C₄alkyl)-Ar, —C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₄ alkyl-N(C₁-C₄alkyl)-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het and —C₀-C₄alkyl-C₃-C₇ cycloalkyl, where x is 0, 1 or 2, or R¹⁴ and R¹⁵, togetherwith the nitrogen to which they are attached, form a 4-7 memberedheterocyclic ring which optionally contains one or more additionalheteroatoms selected from N, O, and S, wherein said C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl are optionally substituted by one or more of thesubstituents independently selected from the group halo, —OH, —SH, —NH₂,—NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄alkyl)(unsubstituted C₁-C₄ alkyl), unsubstituted —OC₁-C₄ alkyl, —CO₂H,—CO₂(unsubstituted C₁-C₄ alkyl), —CONH₂, —CONH(unsubstituted C₁-C₄alkyl), —CON(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl),—SO₃H, —SO₂NH₂, —SO₂NH(unsubstituted C₁-C₄ alkyl) and—SO₂N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl); or apharmaceutically acceptable salt or solvate thereof.
 19. The compoundaccording to claim 1, wherein: R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ areeach H; U is —OR¹⁰, —COOR¹⁰, —CONR¹¹R¹² or —NR¹¹R¹²; A is a phenyl fusedring; Q is a substituted phenyl group containing one or two substituentsselected from halo, C₁-C₄ alkoxy and C₁-C₄ alkyl or Q is a1,3-benzodioxolyl or a dihydrobenzofuranyl group; p is 1 or 2; n is 2; mis 1; q is 1; k is 0; t is 0; W¹ is aryl; W² is aryl or C₁-C₄ alkyl; andW³ is H; or a pharmaceutically acceptable salt or solvate thereof. 20.The compound according to claim 1, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹ and W³ are each H; U is —OH, —COOH, —CONH₂,—CON(H)CH₂-furan-2-yl, —N(H)CH₂-furan-2-yl; A is a phenyl fused ring; Qis a phenyl group substituted by one or two substituents selected fromchloro, trifluoromethyl and methoxy or Q is a 1,3-benzodioxolyl or adihydrobenzofuranyl group; p is 1 or 2; n is 2; m is 1; q is 1; k is 0;t is 0; W¹ is unsubstituted phenyl; and W² is methyl or unsubstitutedphenyl; or a pharmaceutically acceptable salt or solvate thereof.
 21. Acompound selected from:2-[2-{[2-chloro-3-(trifluoromethyl)-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid,2-[2-{[2,4-dimethoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid,2-[2-{[(2,3-methylenedioxy)benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid,2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid,2-[2-{[4-methoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid,(R)-2-[2-{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid,(R)-2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid,(S)-2-[2-[{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-benzofuranacetic acid,(S)-2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid,2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid,2-[2-{[(2,3-methylenedioxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuranacetic acid,2-[2-{[(2,4-dimethoxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuranacetic acid,2-{2-[(4-methoxy-benzyl)(2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid,2-{2-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl-amino]ethyl}-benzofuran-6-yl)-N-furan-2-ylmethyl-acetamide,2-{2-[(2,4-dimethoxy-benzyl)(2,2-diphenylethyl)-amino]ethyl}-benzofuran-6-yl)-N-furan-2-ylmethyl -acetamide,2-{2-[(2(chloro-3-(trifluoromethyl)-benzyl)(2,2-diphenylethyl-amino]ethyl}-benzofuran-6-yl)-acetamide,(racemic)2-{3-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2-phenyl-propyl)-amino]-propyl}-benzofuran-6-yl)-aceticacid,2-(2-{3-[(2-chloro-3-(trifluoromethyl)-benzyl-(2,2-diphenylethyl)-amino]-propyl}-benzofuran-6-yl)-ethanol,2-(2-{3-[(2,4-dimethoxy)-benzyl-(2,2-diphenylethyl)-amino]-propyl}-benzofuran-6-yl)-ethanol,2-{3-[(2-chloro-3-(trifluoromethyl)-benzyl)-((R)-2-phenyl-propyl)-amino]-propyl}-benzofuran-6-yl)-aceticacid,2-{3-[(2-chloro-3-(trifluoromethyl)-benzyl)-((S)-2-phenyl-propyl)-amino]-propyl}-benzofuran-6-yl)-aceticacid,(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-{2-[(furan-2-ylmethyl)-amino]-ethyl-benzofuran-2-yl)-propyl]-amine,and a stereoisomer, a stereoisomeric mixture or racemate thereof and apharmaceutically acceptable salt or solvate thereof.
 22. The compoundaccording to claim 21, selected from:2-[2-{[2,4-dimethoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid,(R)-2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid,2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid,2-[2-{[(2,4-dimethoxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuran acetic acid, and a stereoisomer, a stereoisomeric mixture orracemate thereof and a pharmaceutically acceptable salt or solvatethereof.
 23. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier ordiluent.
 24. (canceled)
 25. A method for the prevention or treatment ofan LXR mediated disease or condition comprising administering atherapeutically effective amount of a compound according to claim
 1. 26.The method according to claim 25, wherein said LXR mediated disease orcondition is cardiovascular disease.
 27. The method according to claim25, wherein said LXR mediated disease or condition is atherosclerosis.28. The method according to claim 25, wherein said LXR mediated diseaseor condition is inflammation.
 29. A method for increasing reversecholesterol transport, said method comprising administering atherapeutically effective amount of a compound according to claim
 1. 30.A method for inhibiting cholesterol absorption, said method comprisingadministering a therapeutically effective amount of a compound accordingto claim
 1. 31-38. (canceled)
 39. A compound selected from the group:2-[2-[(2,2-diphenylethyl)amino]ethyl]-5-benzofuran acetic acid methylester,2-[2-[[2-chloro-3-(trifluoromethyl)benzyl-(2,2-diphenylethyl)amino]ethyl]-5-benzofuranacetic acid methyl ester,2-[2-{[2,4-dimethoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid methyl ester,2-[2-{[(2,3-methylenedioxy)benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid methyl ester, 2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuran acetic acid methyl ester,2-[2-{[4-methoxy-benzyl](2,2-diphenylethyl)amino}ethyl]-5-benzofuranacetic acid methyl ester,(R)-2-[2-[(2-methyl-2-phenylethyl)amino]ethyl]-5-benzofuran acetic acidmethyl ester,(R)-2-[2-{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid methyl ester,(R)-2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid methyl ester,(S)-2-[2-[(2-methyl-2-phenylethyl)amino]ethyl]-5-benzofuran acetic acidmethyl ester,(S)-2-[2-[{[2-chloro-3-(trifluoromethyl)-benzyl](2-methyl-2-phenylethyl)amino}ethyl]-benzofuranacetic acid methyl ester,(S)-2-[2-{[(2,3-dihydrobenzo[b]furan)methyl](2-methyl-2-phenylethyl)amino}ethyl]-5-benzofuranacetic acid methyl ester,2-{2-[(2,2-diphenylethyl)amino]-ethyl}-6-benzofuran acetic acid methylester,2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid methyl ester,2-[2-{[(2,3-methylenedioxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuranacetic acid methyl ester,2-[2-{[(2,4-dimethoxy)benzyl](2,2-diphenylethyl)amino}ethyl]-6-benzofuranacetic acid methyl ester,2-{2-[(4-methoxy-benzyl)(2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid methyl ester, and a stereoisomer, a stereoisomeric mixtureor racemate thereof and a pharmaceutically acceptable salt or solvatethereof.